Dibenzo[a,g]quinolizinium derivatives and the salts thereof

ABSTRACT

The present invention provides a 5,6-dihydrodibenzo[a,g]quinolizinium derivative and the salts thereof of formula (I) which specifically inhibits the sterol 14-reductase which is involved in the distal pathway of cholesterol biosynthesis, and the use of the compound of formula (I) for treating hypercholesterolaemia or hyperlipidaemia. ##STR1## wherein, R 1  and R 2  which may be the same or different from each other, represent a hydroxy group or an alkoxy group having 1 to 4 carbons or R 1  and R 2  together represent a methylenedioxy group; 
     R 3  represents a hydroxy group or an alkoxy group having 1 to 4 carbons; 
     R 4  represents a hydrogen atom, an alkyl group having 1 to 8 carbons, or an alkenyl group having 3 to 8 carbons; 
     X represents inorganic acid ion, organic acid ion or halide, more particularly, nitrate, sulfate, acetate, tartrate, maleate, succinate, citrate, fumarate, aspartate, salicylate, glycerate, ascorbate, fluoride, chloride, iodide or bromide, 
     Z represents an alkyl group having 5 to 12 carbons, or an alkenyl group having 4 to 6 carbons, a N-benzotriazolyl group, a quinolinyl group, a furyl group, a substituted furyl group, or a radical represented by the formula ##STR2## wherein Z 1 , Z 2 , Z 3 , Z 4  and Z 5  which may be the same or different from each other, represent a hydrogen atom, halogen, an alkyl group having 1 to 5 carbons, a trifluoromethyl group, a phenyl group, a substituted phenyl group, a nitro group, an alkoxy group having 1 to 4 carbons, a methylenedioxy group, a trifluoromethoxy group, a hydroxy group, a benzyloxy group, a phenoxy group, a vinyl group, a benzenesulfonylmethyl group or a methoxycarbonyl group; and 
     A and B which may be the same or different from each other, represent carbon or nitrogen.

TECHNICAL FIELD

The present invention relates to 5,6-dihydrodibenzo[a,g]quinoliziniumderivatives and the salts thereof More specifically, the presentinvention relates to 5,6-dihydrodibenzo[a,g]quinolizinium derivativesand the salts thereof which specifically inhibit sterol 14-reductasewhich is involved in the distal pathway of cholesterol biosynthesis, andthus exert cholesterol biosynthesis inhibiting effect. The presentinvention also relates to the use of5,6-dihydrodibenzo[a,g]-quinolizinium derivatives and the salts thereofwhich are represented by formula (I) as set forth below for treatinghypercholesterolemia or hyperlipidaemia.

BACKGROUND ART

Cholesterol is an important vital constituent of cell membrane in mammaland is involved in cell division, growth, development and control ofdifferentiation, and also is a precursor of various essentialmetabolites (for example, steroid hormones, bile acids). However, it maycause hyperlipidaemia which leads to atherosclerosis if its intake orproduction within the body is excess. Hyperlipidaemia leads tocardiovascular disease which is a leading cause of death in humans. Itis usually caused when cholesterol or triglyceride exceeds a properlevel (i.e., total cholesterol level for adults at the age of between 30and 40 is about 200 mg/dl), and then, is deposited to the inner wall ofan artery to form atheroma plaques, thereby blood flow being inhibitedwhich causes cardiac failure or cerebral stroke. Cholesterol issynthesized mainly in the liver in mammals and the synthetic pathwaythereof is started from acetyl-CoA and is completed after at least 32steps of enzymatic reactions.

Cholesterol biosynthesis which occurs in mammal can be summarizedaccording to the enzyme reaction patterns in which each intermediate isformed as in the following reaction scheme 1. ##STR3##

In the above reaction scheme, steps I and II undergo polymerization, andsteps II and III undergo cyclization. In step IV, transformation,demethylation, isomerization or reduction of steroid ring is proceeded.Cholesterol biosynthesis is carefully controlled by the multi-stepregulation, i.e., the so-called multivalent coordinate regulation. Forexample, 3-β-hydroxymethylglutaryl-CoA reductase (HMG--CoA reductase) isthe main rate-limiting enzyme in the cholesterol biosynthesis. Itreduces HMG--CoA synthesized from acetyl-CoA during the early stage ofthe biosynthetic pathway starting from acetate (C2) to mevalonate (C6)and is inhibited in vivo by the final product, cholesterol. Morespecifically, the activity of this enzyme is controlled by dietarycholesterol, oxysteroids and mevalonate derivatives in a feed-backinhibition manner. For the past decade, the lipid-lowering agents havebeen developed based on their inhibiting activities against this enzyme.Most of currently marketed therapeutic agents for hyperlipidaemia whichhave been developed based on such mechanism include, for example,statins such as lovastatin, pravastatin, simvastatin, atorvastatin, andcerivastatin. However, if cholesterol biosynthesis is suppressed byinhibiting the activity of EMG--CoA reductase which is the rate limitingenzyme at the early stage of cholesterol biosynthesis, there may be manyside effects that the synthesis of many important biomolecules such asdolicol, isopentenyl pyrophosphate, haem A, and ubiquinone which arealso derived from mevalonate are suppressed together.

Therefore, it may be advantageous to block cholesterol biosynthesis at astep distal to HMG--CoA reductase in order to prevent depletion of suchessential intermediates.

Accordingly, recent researches have been focused on the development ofnew type of therapeutic agents for hyperlipidaemia which can effectivelyblock only the post-squalene steps without interfering HMG--CoAreductase activity. For example, the activation mechanisms of the distalenzymes responsible for the post-squalene pathway in the cholesterolbiosynthesis which comprises the sequence of`squalene→lanosterol→zymosterol→desmosterol→cholesterol` have beenstudied, and some attempts to screen and develop a drug which canspecifically inhibit the activity of the target enzyme responsible forthe distal pathway of cholesterol biosynthesis, have been made.Especially, based on the inhibitory activity of squalene epoxidaseresponsible for the pathway of `squalene→lanosterol`, a benzylamineseries compound, NB598 has been developed by Banyu Pharmaceutical Co. ofJapan; Squalenestatin I has been developed by the researchers of GlaxoWellcome Limited, a British company on the basis of its inhibition ofsqualene synthase which is responsible for the synthesis of squalenefrom farnesyl pyrophosphate. RPR107393 has been developed as a potentsqualene synthase inhibitor by researchers at Rhone-Poulenc, France.Further, Taton et al. have reported MDL 28,815 having 8-azadecaline ringbased on the inhibition of 2,3-oxidosqualene cyclase responsible for thecyclization reaction in which squalene epoxide is converted intomethylsterol (See, Biochem. Biophys. Res. Commun. 1986, 138, 764-70).These NB598, Squalenestatin I, RPR107393 and MDL 28,815 which inhibitthe activities of enzymes responsible for the post-mevalonate pathway inthe cholesterol biosynthetic pathway have a merit that they canselectively inhibit the cholesterol biosynthesis without effecting onthe production of other important intermediates which are derived frommevalonate, differently from the drugs that target HMG--CoA reductaseresponsible for the early stage of cholesterol biosynthesis.

However, these agents have not yet been commercialized as therapeuticagents for hyperlipidaemia.

DISCLOSURE OF THE INVENTION

The present inventors have conducted an extensive research for manyyears in order to develop a novel class of cholesterol biosyntheticinhibitor which specifically inhibits the enzyme involved in the step of`lanosterol→cholesterol`. As a result, the inventors have surprisinglydiscovered that 5,6-dihydrodibenzo-[a,g]quinolizinium derivatives andthe salts thereof which are represented by formula (I) as set forthhereinafter strongly inhibit the activity of sterol 14-reductase whichcatalyzes the reduction of 4,4-dimethyl-8,14-dien-3β-ol and thus havecompleted the present invention.

Based on this findings, it was possible to provide a cholesterolbiosynthesis inhibitor which comprises5,6-dihydrodibenzo[a,g]quinolizinium derivatives and the salts thereofwhich are represented by formula (I) as the main component whichspecifically inhibits the sterol 14-reductase in the distal pathway ofthe cholesterol biosynthesis.

It is therefore an object of the present invention to provide5,6-dihydrodibenzo[a,g]quinolizinium derivatives or the salts thereofwhich are represented by formula (I) as set forth below.

Another object of the present invention is to provide a cholesterolbiosynthesis inhibitor which comprises5,6-dihydrodibenzo[a,g]quinolizinium derivatives and the salts thereofwhich are represented by formula (I).

Further object of the present invention is to provide a pharmaceuticalcomposition for treating hyperlipidaemia which comprises5,6-dihydrodibenzo[a,g]quinolizinium derivatives and the salts thereofwhich are represented by formula (I) and a pharmaceutically acceptableexcipient.

Still another object of the present invention is to provide a method fortreating hyperlipidaemia by inhibiting cholesterol biosynthesis,especially inhibiting sterol 14-reductase with the above pharmaceuticalcomposition.

Further objects and advantages of the invention will become apparentthrough reading the remainder of the specification.

The foregoing has outlined some of the more pertinent objects of thepresent invention. These objects should be construed to be merelyillustrative of some of the more pertinent features and applications ofthe invention. Many other beneficial results can be obtained by applyingthe disclosed invention in a different manner or modifying the inventionwithin the scope of the disclosure. Accordingly, other objects and amore thorough understanding of the invention may be had by referring tothe detailed description of the preferred embodiment in addition to thescope of the invention defined by the claims.

Hereinbelow, the application will be illustrated in more detail.

5,6-Dihydrodibenzo[a,g]quinolizinium derivatives and the salts thereofaccording to the present invention have the similar chemical structureto the coridaline-series alkaloids in the form of quaternary ammoniumsalt which are major active components of Corydalis TurtschaninowiiBesser. Corydalis Turtschaninowii Besser is an annual plant widelydistributed in the mountains and fields of Korea and has been used inthe prescription of sedative agent or hemostatic agent in herbalmedicine. This coridaline in the form of a quaternary ammonium salt hasbeen known to have a week sedative action and a strong gastric juicesecretion action, and UK Patent No. 1,265,627 and German Patent No.2,043,218 disclose its use as an anti-ulcer agent.

The inventors of the present invention have discovered the novelcompound of the present invention in the course of screening newcholesterol biosynthesis inhibitor.

This discovery was fully supported by a screening method for theactivity of sterol 14-reductase that was established by the inventorssince the inventors have started the research for a new drug.

The detailed screening method will be explained in detail in the workingexamples. Thus, the principle thereof will be briefly explained below.

That is, sterol 14-reductase is one of the main regulatory enzymes forlanosterol→cholesterol pathway and is responsible for reduction of thedouble bond formed when a methyl group attached to the carbon at14-position of lanosterol is demethylated. First, a screening system forsterol 14-reductase was constructed in which4,4-dimethyl-5α-cholesta-7,14-dien-3β-ol is used as a substrate andthen, the effect on the activity of sterol 14-reductase was investigatedin the screening system. It is possible to obtain the correlation that asubstance inhibiting the activity of sterol 14-reductase inhibitscholesterol biosynthesis by comparing the results obtained from thescreening tests with those of the actual animal experiments.

Dibenzo[a,g]quinolizinium derivative for the purpose of the presentinvention can be represented by the formula (I) below. ##STR4## wherein,R¹ and R² which may be the same or different from each other, representa hydroxy group or an alkoxy group having 1 to 4 carbons or R¹ and R²together represent a methylenedioxy group;

R³ represents a hydroxy group or an alkoxy group having 1 to 4 carbons;

R⁴ represents a hydrogen atom, an alkyl group having 1 to 8 carbons, oran alkenyl group having 3 to 8 carbons;

X represents inorganic acid ion, organic acid ion or halide, moreparticularly, nitrate, sulfate, acetate, tartrate, maleate, succinate,citrate, fumarate, aspartate, salicylate, glycerate, ascorbate,fluoride, chloride, iodide or bromide,

Z represents an alkyl group having 5 to 12 carbon, or an alkenyl grouphaving 4 to 6 carbon, a N-benzotriazolyl group, a quinolinyl group, afuryl group, a substituted furyl group, or a group represented by theformula ##STR5## wherein Z¹, Z², Z³, Z⁴ and Z⁵ which may be the same ordifferent from each other, represent a hydrogen atom, halogen, an alkylgroup having 1 to 5 carbons, a trifluoromethyl group, a phenyl group, asubstituted phenyl group, a nitro group, an alkoxy group having 1 to 4carbons, a methylenedioxy group, a trifluoro-methoxy group, a hydroxygroup, a benzyloxy group, a phenoxy group, a vinyl group, abenzenesulfonylmethyl group or a methoxycarbonyl group; and

A and B which may be the same or different from each other, representcarbon or nitrogen.

The cholesterol biosynthesis inhibitor according to the presentinvention, especially 5,6-dihydrodibenzo[a,g]quinolizinium derivativesor the salts thereof as the inhibitor of sterol 14-reductase canpreferably be represented by Table 1 below:

                                      TABLE 1                                     __________________________________________________________________________                                           Formula Ia                                -                                                                          Comp. no.                                                                          R.sup.1                                                                           R.sup.2                                                                           R.sup.3                                                                          R.sup.4                                                                         Z               X    m.p.(° C.)                      __________________________________________________________________________     1   OMe OMe OMe                                                                              Et                                                                              --CH.sub.2 (CH.sub.2).sub.10 CH.sub.3                                                         Cl   150                                       -  2 OMe OMe OMe Et                                                                                                 Cl 102                                  -  3 OMe OMe OMe Et                                                                                                 Cl 72 #                                 -  4 OMe OMe OMe Et                                                                                                 Cl 210                                  -  5 OMe OMe OMe Et                                                                                                 Cl 100 #                                -  6 OMe OMe OMe Et                                                                                                 Cl 85 ##                                -  7 OMe OMe OMe Et                                                                                                 Cl 175 #                                -  8 OMe OMe OMe Et                                                                                                 Cl 82 ##                                -  9 OMe OMe OMe Et                                                                                                 Cl 115 #                                - 10 OMe OMe OMe Et                                                                                                 Cl 76 ##                                - 11 OMe OMe OMe Et                                                                                                 Cl 117 #                                - 12 OMe OMe OMe Et                                                                                                 Cl 70 ##                                - 13 OMe OMe OMe Et                                                                                                 Cl 85 ##                                - 14 OMe OMe OMe Et                                                                                                 Cl 71 ##                                - 15 OMe OMe OMe Et                                                                                                 Cl 72 ##                                - 16 OMe OMe OMe Et                                                                                                 Cl 83 ##                                - 17 OMe OMe OMe Et                                                                                                 Cl 114 #                                - 18 OMe OMe OMe Et                                                                                                 Cl 165 #                                - 19 OMe OMe OMe Et                                                                                                 Cl 186 #                                - 20 OMe OMe OMe Et                                                                                                 Cl 72 ##                                - 21 OMe OMe OMe Et                                                                                                 Cl 76 ##                                - 22 OMe OMe OMe Et                                                                                                 Cl 75 ##                                - 23 OMe OMe OMe Et                                                                                                 Cl 92 ##                                - 24 OMe OMe OMe Et                                                                                                 Cl 131 #                                - 25 OMe OMe OMe Et                                                                                                 Cl 98 ##                                - 26 OMe OMe OMe Et --CH═CH.sub.2 Cl 91                                   - 27 OMe OMe OMe Et                                                                                                 Cl 167 #                                - 28 OMe OMe OMe Et                                                                                                 Cl 87 ##                                - 29 OMe OMe OMe Et                                                                                                 Cl 89 ##                                - 30 OMe OMe OMe Et                                                                                                 Cl 85 ##                                - 31 OMe OMe OMe Et                                                                                                 Cl 87 ##                                - 32 OMe OMe OMe Et                                                                                                 Cl 76 ##                                - 33 OMe OMe OMe Et                                                                                                 Cl 85 ##                                - 34 OMe OMe OMe Et                                                                                                 Cl 95 ##                                - 35 OMe OMe OMe Et                                                                                                 Cl 135 #                                - 36 OMe OMe OMe Et                                                                                                 Cl 104 #                                - 37 OMe OMe OMe Et                                                                                                 Cl 110 #                                - 38 OMe OMe OMe Et                                                                                                 Cl 100 #                                - 39 OMe OMe OMe Et                                                                                                 Cl 85 ##                                - 40 OMe OMe OMe Et                                                                                                 Cl 105 #                                - 41 OMe OMe OMe Et                                                                                                 Cl 195 #                                - 42 OMe OMe OMe Et                                                                                                 Cl 103 #                                - 43 OMe OMe OMe Et                                                                                                 Cl 110 #                                - 44 OMe OMe OMe Et                                                                                                 Cl 195 #                                -                                                                          45   --O--CH.sub.2 --O--                                                                   OMe                                                                              Et                                                                              --CH.sub.2 (CH.sub.2).sub.10 CH.sub.3                                                         I    175                                       - 46 --O--CH.sub.2 --O-- OMe Et                                                                                     I 155 ##                                - 47 --O--CH.sub.2 --O-- OMe Et                                                                                     I 112 ##                                - 48 --O--CH.sub.2 --O-- OMe Et                                                                                     I 132 ##                                - 49 --O--CH.sub.2 --O-- OMe Et                                                                                     I 115 ##                                - 50 --O--CH.sub.2 --O-- OMe Et                                                                                     I 142 ##                                - 51 --O--CH.sub.2 --O-- OMe Et                                                                                     I 134 ##                                - 52 --O--CH.sub.2 --O-- OMe Et                                                                                     I 136 ##                                - 53 --O--CH.sub.2 --O-- OMe Et                                                                                     I 115 ##                                - 54 --O--CH.sub.2 --O-- OMe Et                                                                                     I 139 ##                                -                                                                          55   OEt OEt OMe                                                                              Et                                                                               ##STR58##      Cl   132                                    56 OEt OEt OMe Et                                                              ##ST Cl 100                                                                     - 57 OEt OEt OMe Et                                                              ##S Cl 113                                                                 - 58 OEt OEt OMe Et                                                                  ##S Cl 126                                                             - 59 OH OH OMe Et                                                                        ## Cl 82                                                           - 60 OH OH OMe Et                                                                           # Cl 88 #                                                       - 61 OEt OEt OEt Et --CH.sub.2 (CH.sub.2).sub.10 CH.sub.3 Cl 174                               - 62 OEt OEt OEt Et                                                          ##STR64##       Cl 142                                        - 63 OEt OEt OEt Et                                                                                           ##ST Cl 127                                   - 64 OEt OEt OEt Et                                                                                                 Cl 110 #                                - 65 OEt OEt OEt Et                                                                                                 Cl 136 #                                - 66 OPr OPr OPr Et                                                                                                 Cl 133 #                                - 67 OPr OPr OPr Et                                                                                                 Cl 122 #                                - 68 OPr OPr OPr Et                                                                                                 Cl 151 #                                - 69 OMe OMe OMe Et                                                                                                 HSO.sub.4 .sup.- 123                    - 70 OMe OMe OMe Et                                                                                                 CH.sub.3 CO.sub.2 .sup.- 108                                                  - 71 OMe OMe OMe Et                                                           NO.sub.3 .sup.- 127                  __________________________________________________________________________

The compounds represented by the formula (I) according to the presentinvention can be synthesized starting from the compound of formula (II)below according to the reaction scheme 2 described below. ##STR74##wherein, R¹, R², R³, R⁴, X and Z are the same as defined in the compoundof formula (I) above.

In the first step of the reaction scheme,5,6-dihydrodibenzo[a,g]quinolizinium salt of formula (II) is reactedwith acetone in the presence of a base such as sodium hydroxide to give8-acetonyl-5,6-dihydrodibenzo[a,g]quinolizine compound of the formula(III).

In the second step, 8-acetonyl-5,6-dihydrodibenzo[a,g]quinolizinecompound and allyl halide (R⁴ --X) are reacted at 50˜100° C. in a polarsolvent such as acetonitrile or a non-polar solvent such as toluene togive 13-alkyl-5,6-dihydrodibenzo[a,g]quinolizinium salt of formula (IV).

The third step of the above reaction scheme involves the cleavagereaction of 2,3-methylenedioxy ring or deprotection reaction of2,3-dimethoxy group in which the compound of formula (IV) is reactedwith Lewis acid such as anhydrous aluminum chloride at 80˜160° C. andthen subjected to hydrolysis reaction with a dilute acid. According tothe reaction conditions, 13-alkyl-2,3-dihydroxy compound may be producedas a major product along with 2,3,9-trihydroxy-, or2,3,9,10-tetrahydroxy compound and these compounds can be separated byrecrystallization or column chromatography. However, it may be possibleto use the compound in the fourth step reaction without furtherseparation process.

The fourth step involves a reaction in which the compound of formula (V)obtained from the previous step is selectively alkylated at2,3-positions with an alkylating reagent such as dimethyl sulfate oriodomethane or reacted with dibromomethane to give13-alkyl-9-hydroxy-5,6-dihydrodibenzo[a,g]quinolizinium salt of formula(VI) wherein a methylenedioxy ring is introduced.

In the fifth reaction step, the compound of formula (VI) thus obtainedis reacted with electrophiles (ZCH₂ --X) to give 9-substituted5,6-dihydrodibenzo[a,g]-quinolizinium salt.

The compound of formula (IV) used in preparing the compound of formula(I) may also be synthesized under the different reaction conditionaccording to the reaction scheme 3 below. ##STR75## wherein, R¹, R², R³,R⁴ and X are the same as defined in the compound of formula (I) above.

According to the reaction scheme 3, 1.0 mol of5,6-dihydrodibenzo[a,g]-quinolizinium salt of the formula (II) isreacted with 1.0 to 3.0 mol of NaBH₄ and 2.0 to 4.0 mol of potassiumcarbonate in an alcoholic solvent to give a compound of the formula(VII) and the compound thus obtained is then reacted with 1.0 to 3.0 molof electrophiles (R⁴ --X) in an organic solvent to give13-alkyl-dibenzo-[a,g]quinolizinium salt of the formula (VIII). Compound(VIII) is then oxidized with N-chlorosuccin imide (NCS) or N-bromosuccinimide to give 13-substituted 5,6-dihydrodibenzo[a,g]quinolizinium saltof the formula (IV).

In addition, the compound of formula (I) may also be synthesized underthe different reaction condition according to the reaction scheme 4below. ##STR76## wherein, R¹, R², R³, R⁴, X and Z are the same asdefined in the compound of formula (I) above.

According to the reaction scheme 4, 1.0 mol of the compound of theformula (IV) is subjected to pyrolysis in the presence of a non-polarsolvent such as decaline or in the absence of a solvent at a hightemperature of 100 to 300° C. to give a compound of the formula (VI) andthe compound thus obtained is then reacted with 1.0 to 2.0 mol ofelectrophiles (ZCH₂ --X) to give 9-substituted5,6-dihydrodibenzo[a,g]quinolizinium salt of the formula (I).

9-Substituted 5,6-dihydrodibenzo[a,g]quinolizinium salt of the formula(I) may be transformed into various salts such as halide, sulfate,nitrate, acetate, cinnamate, tinate, tannate, maleate, succinate,citrate, fumarate or fatty acid salt, etc. on the basis of the saltsused in the purification process of the reaction scheme 5 describedbelow. ##STR77## wherein, R¹, R², R³, R⁴, X and Z are the same asdefined in the compound of formula (I) above; and Y represent halide,sulfate, nitrate, cinnamate, tinate, tannate, maleate, succinate,citrate, fumarate, or fatty acid salt ion.

In the above reaction scheme, substituted5,6-dihydrodibenzo[a,g]-quinolizinium salt of the formula (I) is reactedwith acetone in the presence of a base such as sodium hydroxide to give8-acetonyl-5,6-dihydrodibenzo[a,g]-quinolizine compound of the formula(IX) and the compound thus obtained is reacted with a suitable inorganicacid, organic acid or fatty acid to give various5,6-dihydrodibenzo[a,g]-quinolizinium compounds of formula (X).

Among 5,6-dihydrodibenzo[a,g]-quinolizinium salts of formula (I), thecompound wherein R¹, R², R³, R⁴ and X each represents a methoxy group, amethoxy group, a methoxy group, an ethyl group and chloride, and Zrepresents 4-(tert-butyl)phenyl; the compound wherein R¹, R², R³, R⁴ andX each represents a methoxy group, a methoxy group, a methoxy group, anethyl group and chloride, and Z represents 4-pentafluorophenyl; thecompound wherein R¹, R², R³, R⁴ and X each represents a methoxy group, amethoxy group, a methoxy group, an ethyl group and chloride, and Zrepresents 4-trifluoromethylphenyl; and the compound wherein R¹ -R², R³,R⁴ and X each represents a methylenedioxy group, a methoxy group, anethyl group and iodide, and Z represents 4-trifluoromethylphenyl arepreferred in an aspect of the pharmaceutical efficacy.

The compound of formula (I) markedly inhibits the cholesterolbiosynthesis in the cultured human liver cell culture (HepG2 cell line).In order to investigate the effect of the compound of formula (I) of theinvention, the compound was orally administered into male Syrian GoldenHamsters having weights of 90˜110 g for two weeks and blood was thentaken from each animal. Plasma lipids, i.e., total cholesterol,LDL-cholesterol, HDL-cholesterol and triglycerides were analyzed usingan automatic analyzer (Automatic analyzer model Hitachi 7150). As theresults, total cholesterol, LDL-cholesterol, and triglyceride levelswere significantly decreased while HDL-cholesterol value was notsignificantly changed. In addition, the compound resulted in decrease ina certain degree in the glucose value within the serum.

The compound of formula (I) may be formulated into a pharmaceuticalcomposition with pharmaceutically acceptable excipients or carriers.Especially, the composition can desirably be used as the therapeuticagents for treating hypercholesterolemia and hyperlipidaemia byinhibiting sterol 14-reductase. The composition may be formulated into atablet, a syrup or an injection formulation, and thus, can beadministered orally or parenterally. An effective dose will varydepending upon the kind of the excipients or carriers within the rangefor treating hypercholesterolemia and hyperlipidaemia with a dose of0.1˜50 mg/kg/day of active ingredient being preferable in case of oraladministration.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in greater detail by way of thefollowing examples and synthetic examples. The examples are provided forthe purpose of illustration only and should not be construed as limitingthe invention which is properly delineated in the claims.

SYNTHETIC EXAMPLES

Hereinbelow, synthetic examples for the derivative of the compoundsrepresented by the above formula (I) will be described.

Example 1 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-dodecoxy-13-ethyl-10-methoxybenzo[g]quinoliziniumchloride (Compound No. 1)

10 G of5,6-dihydro-2,3-methylenedioxybenzo[a]-9,10-dimethoxy-13-ethyl-benzo[g]quinoliziniumchloride and 10 g of aluminum chloride were suspended in 70 ml ofdichloromethane and the mixture was stirred for 1 hour. The reactionmixture was concentrated under reduced pressure to remove the solvent. A15% hydrochloric acid solution was added to the mixture and theprecipitate produced was filtered, washed and dried to give 9 g of5,6-dihydro-2,3-dihydroxybenzo[a]-13-ethyl-9-hydroxy-10-methoxybenzo[g]quinoliziniumchloride as a light orange crystal.

10 G of5,6-dihydro-2,3-dihydroxybenzo[a]-13-ethyl-9-hydroxy-10-methoxybenzo[g]quinoliziniumchloride were suspended in 150 ml of water and 20 g of a 50% sodiumhydroxide solution and 20 ml of dimethylsulfate were added thereto.After the mixture was stirred for 5 hours, a 15% hydrochloric acidsolution was added to adjust pH to neutral. The precipitate thusproduced was filtered to give 8 g of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-9-hydroxy-10-methoxybenzo-[g]quinoliziniumchloride as a light brown crystal.

1 G of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-9-hydroxy-10-methoxybenzo[g]quinoliziniumchloride, 0.45 g of sodium iodide, and 0.41 g of potassium carbonatewere dissolved in 10 ml of acetonitrile. After 0.7 g of dodecyl bromidewas then added thereto, the mixture was refluxed for 8 hours.Undissolved by-products were filtered off and the filtrate wasconcentrated under reduced pressure to remove the solvent. The residuewas then dissolved in chloroform and washed with 10 ml of water. Thesolution was dried over magnesium sulfate to remove water and theresidue was then purified by silica gel column chromatography elutingwith a mixed solvent of chloroform/methanol (15:1) to give 0.24 g of thetitled compound as a brown crystal (m.p.: 150° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 0.87 (t, J=6.9Hz, 3H), 1.26 (m, 12H), 150(m, 4H), 1.68 (t, J=7.2 Hz, 3H), 1.98 (m, 4H), 3.35 (m, 2H), 3.41 (m,2H), 3.96 (s, 3H), 4.00 (s, 3H), 4.01 (s, 3H), 4.50 (t, J=6.9 Hz, 2H),5.10 (m, 2H), 6.91 (s, 1H), 7.29 (s, 1H), 8.01 (d, J=9.3 Hz, 1H), 8.13(d, J=9.3 Hz, 2H), 10.00 (s, 1H)

Example 2 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-[4-(tert-butyl)benzyloxy]-13-ethyl-10-methoxybenzo[g]quinoliziniumchloride (Compound No. 2)

The process of Example 1 was repeated except that 0.6 g of4-(tert-butyl)benzyl bromide was employed in place of dodecyl bromide togive 0.47 g of the titled compound as a brown crystal (m.p.: 102° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.29 (s, 9H), 1.69 (t, J=7.2 Hz, 3H), 3.20(m, 2H), 3.39 (m, 2H), 3.94 (s, 3H), 3.99 (s, 3H), 4.11 (s, 3H), 4.98(m, 2H), 5.53 (s, 2H), 6.95 (s, 1H), 7.23 (s, 1H), 7.42 (d, J=8.1 Hz,2H), 7.64 (d, J=8.1 Hz, 2H), 8.04 (d, J=9.3 Hz, 1H), 8.87 (d, J=9.3 Hz,1H), 10.00 (s, 1H)

Example 3 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,4,5,6-pentafluoro)benyloxybenzo[g]quinoliziniumchloride (Compound No. 3)

The process of Example 1 was repeated except that 0.7 g of2,3,4,5,6-pentafluorobenzyl bromide was employed in place of dodecylbromide to give 0.80 g of the titled compound as a brown crystal (m.p.:72° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.67 (t, J=7.8 Hz, 3H), 3.37 (m, 2H), 3.42(m, 2H), 3.96 (s, 1H), 4.01 (s, 3H), 4.08 (s, 3H), 5.06 (m, 2H), 5.86(s, 2H), 6.93 (s, 1H), 7.28 (s, 1H), 7.92 (d, J=9.3 Hz, 1H), 8.04 (d,J=9.3 Hz, 1H), 10.12 (s, 1H).

Example 4 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-9-[4-fluoro-2-(trifluoromethyl)benzyloxy]-10-methoxybenzo[g]-quinoliziniumchloride (Compound No. 4)

The process of Example 1 was repeated except that 0.68 g of4-fluoro-2-(trifluoromethyl)benzyl bromide was employed in place ofdodecyl bromide to give 0.76 g of the titled compound as a brown crystal(m.p.: 210° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.68 (t, J=6.6 Hz, 3H), 3.28 (m, 2H), 3.41(m, 2H), 3.96 (s, 3H), 4.00 (s, 3H), 4.05 (s, 3H), 5.05 (m, 2H), 5.77(s, 2H), 6.94 (s, 1H), 7.26 (s, 1H), 7.40 (m, 1H), 7.46 (m, 1H), 7.97(d, 1H, J=9.3 Hz), 8.04 (d, J=9.3 Hz, 1H), 8.50 (m, 1H), 10.06 (s, 1H).

Example 5 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-(4,5-dimethoxy-2-nitro)benzyloxy-13-ethyl-10-methoxybenzo[g]-quinoliziniumchloride (Compound No. 5)

The process of Example 1 was repeated except that 0.75 g of4,5-dimethoxy-2-nitrobenzyl bromide was employed in place of dodecylbromide to give 0.36 g of the titled compound as a brown crystal (m.p.:100° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.60 (t, J=7.2 Hz, 3H), 3.21 (m, 2H), 3.39(m, 2H), 3.96 (s, 3H), 3.98 (s, 3H), 4.00 (s, 3H), 4.13 (s, 3H), 4.22(s, 3H), 5.18 (m, 2H), 5.79 (s, 2H), 6.91 (s, 1H), 7.22 (s, 1H), 7.43(s, 1H), 7.69 (s, 1H), 7.91 (d, J=9.0 Hz, 1H), 8.00 (d, J=9.0 Hz, 1H),10.36 (s, 1H).

Example 6 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(4-methyl-3-nitro)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 6)

The process of Example 1 was repeated except that 0.51 g of4-methyl-3-nitrobenzyl chloride was employed in place of dodecyl bromideto give 0.38 g of the titled compound as a brown crystal (m.p.: 85° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.70 (t, J=6.9 Hz, 3H), 2.62 (s, 3H), 3.27(m, 2H), 3.38 (m, 2H), 3.96 (s, 3H), 4.01 (s, 3H), 4.14 (s, 3H), 5.01(m, 2H), 5.78 (s, 2H), 6.91 (s, 1H), 7.25 (s, 1H), 7.45 (d, J=7.8 Hz,1H), 7.92 (d, J=9.6 Hz, 1H), 8.00 (d, J=9.6 Hz, 1H), 8.24 (d, J=9.3 Hz,1H), 8.33 (m, 1H), 10.30 (s, 1H)

Example 7 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(2-methoxy-5-nitro)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 7)

The process of Example 1 was repeated except that 0.67 g of2-methoxy-5-nitrobenzyl bromide was employed in place of dodecyl bromideto give 0.55 g of the titled compound as a brown crystal (m.p.: 175°C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.69 (t, J=6.3 Hz, 3H), 3.31 (m, 2H), 3.42(m, 2H), 3.96 (s, 3H), 4.00 (s, 3H), 4.07 (s, 3H), 4.08 (s, 3H), 5.13(m, 2H), 5.74 (s, 2H), 6.92 (s, 1H), 7.92 (d, J=9.3 Hz, 1H), 8.02 (d,J=9.3 Hz, 1H), 8.25 (d, J=2.7 Hz, 1H), 8.27 (d, J=3.0 Hz, 1H), 8.54 (d,J=3.0 Hz, 1H), 10.09 (s, 1H)

Example 8 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(4-vinyl)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 8)

The process of Example 1 was repeated except that 0.41 g of4-vinylbenzyl chloride was employed in place of dodecyl bromide to give0.33 g of the titled compound as a brown crystal (m.p.: 82° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.69 (t, J=6.8 Hz, 3H), 3.29 (m, 2H), 3.40(m, 2H), 3.95 (s, 3H), 4.00 (s, 3H), 4.12 (s, 3H), 5.01 (m, 2H), 5.40(m, 2H), 5.68 (s, 2H), 6.72 (m, 1H), 6.92 (s, 1H), 7.25 (s, 2H), 7.38(m, 4H), 7.94 (d, J=9.3 Hz, 1H), 7.99 (d, J=9.3 Hz, 1H), 10.00 (s, 1H).

Example 9 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(4-trifluoromethyl)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 9)

The process of Example 1 was repeated except that 0.65 g of4-(trifluoromethyl)benzyl bromide was employed in place of dodecylbromide to give 0.72 g of the titled compound as a brown crystal (m.p.:115° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.66 (t, J=7.5 Hz, 3H), 3.27 (m, 2H), 3.38(m, 2H), 3.96 (s, 3H), 4.00 (s, 3H), 4.10 (s, 3H), 5.08 (m, 2H), 5.79(s, 2H), 6.91 (s, 1H), 7.26 (s, 1H), 7.66 (d, J=9.3 Hz, 2H), 7.88 (d,J=9.3 Hz, 2H), 7.97 (d, J=7.8 Hz, 1H), 8.03 (d, J=7.8 Hz, 1H), 10.24 (s,1H)

Example 10 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-(2-chloro-4-fluro)benzyloxy-13-ethyl-10-methoxybenzo[g]quinoliziniumchloride (Compound No. 10)

The process of Example 1 was repeated except that 0.49 g of2-chloro-4-fluorobenzyl bromide was employed in place of dodecyl bromideto give 0.19 g of the titled compound as a brown crystal (m.p.: 76° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.61 (t, J=6.3 Hz, 3H), 3.31 (m, 2H), 3.40(m, 2H), 3.96 (s, 3H), 4.01 (s, 3H), 4.12 (s, 3H), 4.91 (m, 2H), 5.76(s, 2H), 6.99 (s, 1H), 7.22 (s, 1H), 7.34 (m, 3H), 7.99 (d, J=9.3 Hz,1H), 8.08 (d, J=9.3 Hz, 1H), 9.79 (s, 1H)

Example 11 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(3-trifluoromethyl)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 11)

The process of Example 1 was repeated except that 0.65 g of3-(trifluoromethyl)benzyl bromide was employed in place of dodecylbromide to give 0.42 g of the titled compound as a brown crystal (m.p.:117° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.66 (t, J=6.8 Hz, 3H), 3.34 (m, 2H), 3.38(m, 2H), 3.96 (s, 3H), 4.00 (s, 3H), 4.10 (s, 3H), 5.00 (m, 2H), 5.80(s, 2H), 6.91 (s, 1H), 7.26 (s, 1H), 7.60 (m, 3H), 7.92 (d, J=9.6 Hz,1H), 8.00 (d, J=9.6 Hz, 1H), 8.18 (d, J=6.9 Hz, 1H), 10.23 (s, 1H)

Example 12 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(3-methoxy)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 12)

The process of Example 1 was repeated except that 0.42 g of3-methoxybenzyl chloride was employed in place of dodecyl bromide togive 0.54 g of the titled compound as a brown crystal (m.p.: 70° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.67 (t, J=6.8 Hz, 3H), 3.21 (m, 2H), 3.39(m, 2H), 3.87 (s, 3H), 3.95 (s, 3H), 4.00 (s, 3H), 4.11 (s, 3H), 5.00(m, 2H), 5.61 (m, 2H), 6.99 (s, 1H), 7.24 (s, 1H), 7.27 (m, 4H), 7.95(d, J=9.3 Hz, 1H), 8.00 (d, J=9.3 Hz, 1H), 10.10 (s, 1H).

Example 13 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,5,6-tetrafluoro-4-trifluoromethyl)benzyloxy-benzo[g]quinoliziniumchloride (Compound No. 13)

The process of Example 1 was repeated except that 0.84 g of2,3,5,6-tetrafluoro-4-trifluoromethyl benzyl bromide was employed inplace of dodecyl bromide to give 0.48 g of the titled compound as abrown crystal (m.p.: 85° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.69 (t, J=7.5 Hz, 3H), 3.30 (m, 2H), 3.40(m, 2H), 3.96 (s, 3H), 4.01 (s, 3H), 4.07 (s, 3H), 5.10 (m, 2H), 5.96(s, 2H), 6.92 (s, 1H), 7.25 (s, 1H), 7.91 (d, J=9.3 Hz, 1H), 8.05 (d,J=9.3 Hz, 1H), 10.21 (s, 1H)

Example 14 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-(4-benzyloxy)-benzyloxy-13-ethyl-10-methoxybenzo[g]quinoliziniumchloride (Compound No. 14)

The process of Example 1 was repeated except that 0.63 g of4-benzyloxybenzyl bromide was employed in place of dodecyl bromide togive 0.55 g of the titled compound as a brown crystal (m.p.: 71° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.63 (t, J=7.3 Hz, 3H), 3.41 (m, 4H), 3.96(s, 3H), 3.99 (s, 3H), 4.03 (s, 3H), 5.02 (m, 2H), 5.59 (s, 2H), 5.60(s, 2H), 6.87 (s, 1H), 7.02 (m, 2H), 7.35 (m, 6H), 7.72 (m, 2H), 7.93(d, J=9.3 Hz, 1H), 7.98 (d, J=9.3 Hz, 1H), 9.89 (s, 1H)

Example 15 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-(2,5-dimethyl)benzyloxy-13-ethyl-10-methoxybenzo[g]quinoliziniumchloride (Compound No. 15)

The process of Example 1 was repeated except that 0.42 g of2,5-dimethylbenzyl chloride was employed in place of dodecyl bromide togive 0.54 g of the titled compound as a brown crystal (m.p.: 72° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.68 (t, J=6.3 Hz, 3H), 2.40 (m, 6H), 3.42(m, 4H), 3.95 (s, 3H), 4.00 (s, 3H), 4.10 (s, 3H), 4.96 (m, 2H), 5.70(s, 2H), 6.93 (s, 1H), 7.13 (m, 3H), 7.48 (s, 1H), 7.95 (d, J=9.3 Hz,1H), 8.02 (d, J=9.3 Hz, 1H), 9.88 (s, 1H)

Example 16 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(4-phenyl)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 16)

The process of Example 1 was repeated except that 0.55 g of4-phenylbenzyl chloride was employed in place of dodecyl bromide to give0.51 g of the titled compound as a brown crystal (m.p.: 83° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.65 (t, J=7.5 Hz, 3H), 3.26 (m, 2H), 3.36(m, 2H), 3.95 (s, 3H), 3.99 (s, 3H), 4.13 (s, 3H), 5.04 (m, 2H), 5.71(s, 2H), 6.90 (s, 1H), 7.24 (s, 1H), 7.37 (d, J=7.2 Hz, 2H), 7.41 (d,J=7.5 Hz, 2H), 7.46 (d, J=7.2 Hz, 2H), 7.58 (d, J=7.5 Hz, 2H), 7.86 (d,J=9.3 Hz, 1H), 7.99 (d, J=9.3 Hz, 1H), 10.09 (s, 1H)

Example 17 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-(6-chloropyridine-3-yl)methoxy-13-ethyl-10-methoxybenzo[g]quinoli-ziniumchloride (Compound No. 17)

The process of Example 1 was repeated except that 0.45 g of3-chloromethyl-6-chloropyridine was employed in place of dodecyl bromideto give 0.28 g of the titled compound as a brown crystal (m.p.: 114°C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.67 (t, J=7.5 Hz, 3H), 3.26 (m, 2H), 3.38(m, 2H), 3.96 (s, 3H), 4.01 (s, 3H), 4.12 (s, 3H), 5.13 (m, 2H), 5.78(s, 2H), 6.91 (s, 1H), 7.26 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.91 (d,J=9.6 Hz, 1H), 8.00 (d, J=9.6 Hz, 1H), 8.52 (m, 1H), 8.66 (m, 1H), 10.35(s, 1H)

Example 18 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-(3-chloro)-benzyloxy-13-ethyl-10-methoxybenzo[g]quinoliziniumchloride (Compound No. 18)

The process of Example 1 was repeated except that 0.45 g of3-chlorobenzyl chloride was employed in place of dodecyl bromide to give0.53 g of the titled compound as a brown crystal (m.p.: 165° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.66 (t, J=7.5 Hz, 3H), 3.30 (m, 2H), 3.38(m, 2H), 3.96 (s, 3H), 4.00 (s, 3H), 4.11 (s, 3H), 5.06 (m, 2H), 5.70(s, 2H), 6.91 (s, 1H), 7.25 (s, 1H), 7.38 (m, 4H), 7.92 (d, J=9.3 Hz,1H), 8.00 (d, J=9.3 Hz, 1H), 10.17 (s, 1H)

Example 19 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-(4-bromo)benzyloxy-13-ethyl-10-methoxybenzo[g]quinoliziniumchloride (Compound No. 19)

The process of Example 1 was repeated except that 0.69 g of4-bromobenzyl bromide was employed in place of dodecyl bromide to give0.17 g of the titled compound as a brown crystal (m.p.: 186° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.66 (t, J=7.8 Hz, 3H), 3.22 (m, 2H), 3.37(m, 2H), 3.95 (s, 3H), 4.00 (s, 3H), 4.09 (s, 3H), 5.04 (m, 2H), 5.66(s, 2H), 6.91 (s, 1H), 7.26 (s, 1H), 7.35 (d, J=8.4 Hz, 2H), 7.71 (d,J=8.4 Hz, 2H), 7.88 (d, J=9.6 Hz, 1H), 8.01 (d, J=9.6 Hz, 1H), 10.13 (s,1H)

Example 20 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(2-trifluoromethyl)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 20)

The process of Example 1 was repeated except that 0.65 g of2-trifluoromethyl benzyl bromide was employed in place of dodecylbromide to give 0.66 g of the titled compound as a brown crystal (m.p.:72° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.66 (t, J=7.2 Hz, 3H), 3.31 (m, 2H), 3.39(m, 2H), 3.96 (s, 3H), 4.00 (s, 3H), 4.04 (s, 3H), 5.06 (m, 2H), 5.82(s, 2H), 6.93 (s, 1H), 7.26 (s, 1H), 7.72 (m, 3H), 7.94 (d, J=9.6 Hz,1H), 8.01 (d, J=9.6 Hz, 1H), 8.39 (d, J=7.2 Hz, 1H), 10.03 (s, 1H)

Example 21 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(3-phenoxy)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 21)

The process of Example 1 was repeated except that 0.60 g of3-phenoxybenzyl chloride was employed in place of dodecyl bromide togive 0.40 g of the titled compound as a brown crystal (m.p.: 76° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.66 (t, J=7.5 Hz, 3H), 3.27 (m, 2H), 3.37(m, 2H), 3.96 (s, 3H), 4.00 (s, 3H), 4.03 (s, 3H), 5.09 (m, 2H), 5.67(s, 2H), 6.92 (s, 1H), 6.99 (s, 1H), 7.01 (m, 2H), 7.30 (m, 6H), 7.62(m, 1H), 7.90 (d, J=9.3 Hz, 1H), 7.98 (d, J=9.3 Hz, 1H), 10.10 (s, 1H)

Example 22 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(4-methoxy)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 22)

The process of Example 1 was repeated except that 0.43 g of4-methoxybenzyl chloride was employed in place of dodecyl bromide togive 0.84 g of the titled compound as a brown crystal (m.p.: 75° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.68 (t, J=7.2 Hz, 3H), 3.33 (m, 2H), 3.42(m, 2H), 3.93 (s, 3H), 3.94 (s, 3H), 4.08 (s, 3H), 5.23 (m, 2H), 5.73(s, 2H), 6.80 (s, 1H), 6.95 (s, 1H), 7.24 (d, J=8.9 Hz, 2H), 7.39 (d,J=8.7 Hz, 2H), 7.89 (d, J=9.3 Hz, 1H), 7.97 (d, J=9.3 Hz, 1H), 10.00 (s,1H)

Example 23 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-(2-chloro-6-fluoro)benzyloxy-13-ethyl-10-methoxybenzo[g]quinoliziniumchloride (Compound No. 23)

The process of Example 1 was repeated except that 0.5 g of2-chloro-6-fluorobenzyl chloride was employed in place of dodecylbromide to give 0.54 g of the titled compound as a brown crystal (m.p.:92° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.66 (t, J=7.2 Hz, 3H), 3.46 (m, 4H), 3.96(s, 3H), 4.01 (s, 3H), 4.12 (s, 3H), 5.00 (m, 2H), 5.75 (s, 2H), 6.99(s, 1H), 7.11 (s, 1H), 7.28 (m, 3H), 7.99 (d, J=9.3 Hz, 1H), 8.08 (d,J=9.3 Hz, 1H), 9.74 (s, 1H)

Example 24 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(2-methyl-3-nitro)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 24)

The process of Example 1 was repeated except that 0.51 g of2-methyl-3-nitrobenzyl chloride was employed in place of dodecyl bromideto give 0.45 g of the titled compound as a brown crystal (m.p.: 131°C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.68 (t, J=7.5 Hz, 3H), 2.72 (s, 3H), 3.35(m, 2H), 3.56 (m, 2H), 3.96 (s, 3H), 4.00 (s, 3H), 4.09 (s, 3H), 5.00(m, 2H), 5.85 (s, 2H), 6.90 (s, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.79 (d,J=7.5 Hz, 1H), 7.92 (d, J=9.3 Hz, 1H), 8.03 (d, J=9.3 Hz, 1H), 8.42 (d,J=6.9 Hz, 1H), 10.04 (s, 1H)

Example 25 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(5-methyl-2-nitro)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 25)

The process of Example 1 was repeated except that 0.51 g of5-methyl-2-nitrobenzyl chloride was employed in place of dodecyl bromideto give 0.75 g of the titled compound as a brown crystal (m.p.: 98° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.67 (t, J=7.5 Hz, 3H), 2.60 (s, 3H), 3.27(m, 2H), 3.42 (m, 2H), 3.96 (s, 3H), 4.00 (s, 3H), 4.02 (s, 3H), 5.19(m, 2H), 5.91 (s, 2H), 6.92 (s, 1H), 7.26 (s, 1H), 7.93 (d, J=9.3 Hz,1H), 8.01 (d, J=9.3 Hz, 1H), 8.03 (m, 1H), 8.22 (m, 1H), 10.23 (s, 1H)

Example 26 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-allyloxybenzo[g]quinoliziniumchloride (Compound No. 26)

The process of Example 1 was repeated except that 0.21 g of allylchloride was employed in place of dodecyl bromide to give 0.30 g of thetitled compound as a brown crystal (m.p.: 91° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.67 (t, J=7.5 Hz, 3H), 3.21 (m, 2H), 3.43(m, 2H), 3.96 (s, 3H), 4.00 (s, 3H), 4.08 (s, 3H), 5.11 (m, 3H), 5.30(d, 1H, J=8.4 Hz), 5.50 (d, J=15.7 Hz, 1H), 6.39 (m, 1H), 6.95 (s, 1H),7.26 (s, J=9.3 Hz, 1H), 7.94 (d, J=9.3 Hz, 1H), 8.00 (d, 1H), 10.14 (s,1H)

Example 27 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-(3,4-dimethyl)benzyloxy-13-ethyl-10-methoxybenzo[g]quinoliziniumchloride (Compound No.27)

The process of Example 1 was repeated except that 0.43 g of3,4-dimethylbenzyl chloride was employed in place of dodecyl bromide togive 0.62 g of the titled compound as a brown crystal (m.p.: 167° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.68 (t, J=7.2 Hz, 3H), 2.20 (m. 6H), 3.20(m, 2H), 3.42 (m, 2H), 3.94 (s, 3H), 4.08 (s, 3H), 4.12 (s, 3H), 5.16(m, 2H), 5.59 (s, 2H), 6.93 (s, 1H), 7.21 (m, 4H), 7.94 (m, 2H), 9.99(s, 1H)

Example 28 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-(2,4-dimethyl)benzyloxy-13-ethyl-10-methoxybenzo[g]quinoliziniumchloride (Compound No. 28)

The process of Example 1 was repeated except that 0.43 g of2,4-dimethylbenzyl chloride was employed in place of dodecyl bromide togive 0.59 g of the titled compound as a brown crystal (m.p.: 87° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.68 (t, J=7.2 Hz, 3H), 2.36 (m, 6H), 3.25(m, 2H), 3.45 (m, 2H), 3.93 (s, 3H), 4.07 (s, 3H), 4.10 (s, 3H), 5.20(m, 2H), 5.72 (s, 2H), 6.96 (s, 1H), 7.07 (m, 3H), 7.26 (s, 1H), 7.88(q, J=9.3 Hz, 2H), 9.81 (s, 1H)

Example 29 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-(1H-benzo-triazol-1-yl)methoxy-13-ethyl-10-methoxybenzo[g]-quinoliziniumchloride (Compound No. 29)

The process of Example 1 was repeated except that 0.46 g of1-chloromethyl-1H-benzotriazole was employed in place of dodecyl bromideto give 0.65 g of the titled compound as a brown crystal (m.p.: 89° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.68 (t, J=7.5 Hz, 3H), 3.18 (m, 2H), 3.40(m, 2H), 3.95 (s, 3H), 4.00 (s, 3H), 4.01 (s, 3H), 4.90 (m, 2H), 5.80(s, 2H), 6.90 (s, 1H), 7.09 (s, 1H), 7.41 (m, 2H), 7.67 (m, 1H), 7.84(d, J=9.6 Hz, 1H), 8.01 (d, J=9.6 Hz, 1H), 8.06 (m, 1H), 8.35 (d, J=8.7Hz, 1H), 10.95 (s, 1H)

Example 30 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-9-[4-(i-propyl)benzyloxy]-10-methoxybenzo[g]quinoliziniumchloride (Compound No. 30)

The process of Example 1 was repeated except that 0.46 g of4-i-propylbenzyl chloride was employed in place of dodecyl bromide togive 0.40 g of the titled compound as a brown crystal (m.p.: 85° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.23 (s, 3H), 1.26 (s, 3H), 1.65 (t, J=7.5Hz, 3H), 2.92 (m, 1H), 3.29 (m, 2H), 3.37 (m, 2H), 3.95 (s, 3H), 4.00(s, 3H), 4.12 (s, 3H), 5.00 (m, 2H), 5.62 (s, 2H), 6.92 (s, 1H), 7.25(s, 1H), 7.27 (m, 2H), 7.69 (d, J=8.1 Hz, 2H), 7.93 (d, J=9.3 Hz, 1H),7.99 (d, J=9.3 Hz, 1H), 9.98 (s, 1H)

Example 31 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(4-methyl)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 31)

The process of Example 1 was repeated except that 0.38 g of4-methylbenzyl chloride was employed in place of dodecyl bromide to give0.45 g of the titled compound as a brown crystal (m.p.: 87° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.65 (t, J=7.5 Hz, 3H), 2.35 (s, 3H), 3.28(m, 2H), 3.37 (m, 2H), 3.95 (s, 3H), 4.00 (s, 3H), 4.12 (s, 3H), 5.00(m, 2H), 5.61 (s, 2H), 6.92 (s, 1H), 7.21 (s, 1H), 7.25 (d, J=5.7 Hz,2H), 7.64 (d, J=7.5 Hz, 2H), 7.93 (d, J=9.3 Hz, 1H), 7.98 (d, J=9.3 Hz,1H), 9.95 (s, 1H)

Example 32 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(3-methyl)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 32)

The process of Example 1 was repeated except that 0.38 g of3-methylbenzyl chloride was employed in place of dodecyl bromide to give0.38 g of the titled compound as a brown crystal (m.p.: 76° C).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.66 (t, J=7.8 Hz, 3H), 2.41 (s, 3H), 3.30(m, 2H), 3.52 (m, 2H), 3.96 (s, 3H), 4.00 (s, 3H), 4.13 (s, 3H), 5.01(m, 2H), 5.62 (s, 2H), 6.92 (s, 1H), 7.26 (s, 1H), 7.29 (m, 2H), 7.58(m, 2H), 7.93 (d, J=9.3 Hz, 1H), 8.00 (d, J=9.3 Hz, 1H), 9.97 (s, 1H)

Example 33 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(2-trifluoromethyl)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 33)

The process of Example 1 was repeated except that 0.38 g of2-trifluoromethylbenzyl chloride was employed in place of dodecylbromide to give 0.42 g of the titled compound as a brown crystal (m.p.:85° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.68 (t, J=7.2 Hz, 3H), 2.58 (s, 3H), 3.40(m, 4H), 3.95 (s, 3H), 4.00 (s, 3H), 4.09 (s, 3H), 4.90 (m, 2H), 5.69(s, 2H), 6.92 (s, 1H), 7.24 (s, 1H), 7.26 (m, 2H), 7.79 (m, 2H), 7.94(d, J=9.3 Hz, 1H), 8.01 (d, J=9.3 Hz, 1H), 9.80 (s, 1H)

Example 34 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-(3-bromo)-benzyloxy-13-ethyl-10-methoxybenzo[g]quinoliziniumchloride (Compound No. 34)

The process of Example 1 was repeated except that 0.68 g of3-bromobenzyl chloride was employed in place of dodecyl bromide to give0.52 g of the titled compound as a brown crystal (m.p.: 95° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.60 (t, J=7.5 Hz, 3H), 3.31 (m, 2H), 3.52(m, 2H), 3.96 (s, 3H), 4.00 (s, 3H), 4.11 (s, 3H), 5.06 (m, 2H), 5.69(s, 2H), 6.91 (s, 1H), 7.26 (s, 1H), 7.32 (m, 2H), 7.49 (m, 1H), 7.88(m, 1H), 7.92 (d, J=9.3 Hz, 1H), 8.00 (d, J=9.3 Hz, 1H), 10.15 (s, 1H)

Example 35 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-(3,5-dimethoxy)benzyloxy-13-ethyl-10-methoxybenzo[g]quinoliziniumchloride (Compound No. 35)

The process of Example 1 was repeated except that 0.51 g of3,5-dimethoxybenzyl chloride was employed in place of dodecyl bromide togive 0.26 g of the titled compound as a brown crystal (m.p.: 135° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.68 (t, J=7.8 Hz, 3H), 3.25 (m, 2H), 3.36(m, 2H), 3.84 (s, 6H), 3.95 (s, 3H), 4.00 (s, 3H), 4.11 (s, 3H), 5.04(m, 2H), 5.56 (s, 2H), 6.42 (s, 1H), 6.92 (s, 1H), 6.97 (d, J=2.4 Hz,2H), 7.24 (s, 1H), 7.95 (d, J=9.3 Hz, 1H), 8.00 (d, J=9.3 Hz, 1H), 10.11(s, 1H)

Example 36 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(quinolin-2-yl)methoxybenzo[g]quinoliziniumchloride (Compound No. 36)

The process of Example 1 was repeated except that 0.58 g of2-chloromethyl quinoline was employed in place of dodecyl bromide togive 0.46 g of the titled compound as a brown crystal (m.p.: 104° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.68 (t, J=7.5 Hz, 3H), 3.27 (m, 2H), 3.40(m, 2H), 3.97 (s, 3H), 4.00 (s, 3H), 4.09 (s, 3H), 5.10 (m, 2H), 5.96(s, 2H), 6.92 (s, 1H), 7.25 (s, 1H), 7.56 (m, 2H), 7.73 (m, 2H), 7.94(m, 2H), 8.19 (d, J=8.4 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 10.23 (s, 1H)

Example 37 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(3,4,5-trimethoxy)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 37)

The process of Example 1 was repeated except that 0.59 g of3,4,5-triethoxybenzyl chloride was employed in place of dodecyl bromideto give 0.60 g of the titled compound as a brown crystal (m.p.: 110°C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.68 (t, J=7.5 Hz, 3H), 3.18 (m, 2H), 3.41(m, 2H), 3.84 (s, 3H), 3.87 (s, 3H), 3.95 (s, 3H), 3.95 (s, 3H), 4.00(s, 3H), 4.14 (s, 3H), 5.10 (m, 2H), 5.61 (s, 2H), 6.61 (s, 1H), 6.90(s, 1H), 7.16 (s, 1H), 7.25 (s, 1H), 7.99 (d, J=9.6 Hz, 1H), 8.00 (d,J=9.6 Hz, 1H), 10.21 (s, 1H)

Example 38 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-[4-(phenylsulfonylmethyl)benzyloxy]benzo[g]-quinoliziniumchloride (Compound No. 38)

The process of Example 1 was repeated except that 0.89 g of1-bromomethyl-2-[(phenylsulfonylmethyl)benzene was employed in place ofdodecyl bromide to give 0.68 g of the titled compound as a brown crystal(m.p.: 100° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.67 (t, J=7.8 Hz, 3H), 3.28 (m, 2H), 3.41(m, 2H), 3.96 (s, 3H), 3.99 (s, 3H), 4.26 (s, 3H), 4.96 (m, 4H), 5.67(s, 2H), 6.88 (s, 1H), 7.03 (s, 1H), 7.29 (m, 2H), 7.44 (m, 4H), 7.47(m, 2H), 7.61 (m, 2H), 7.98 (d, J=9.3 Hz, 1H), 8.08 (d, J=9.3 Hz, 1H),8.17 (d, J=6.6 Hz, 1H), 10.00 (s, 1H)

Example 39 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(5-nitrofuran-2-yl)methoxybenzo[g]quinoliziniumchloride (Compound No. 39)

The process of Example 1 was repeated except that 0.56 g of2-bromomethyl-5-nitrofuran was employed in place of dodecyl bromide togive 0.18 g of the titled compound as a brown crystal (m.p.: 85° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.69 (t, J=7.2 Hz, 3H), 3.26 (m, 2H), 3.38(m, 2H), 3.96 (s, 3H), 4.01 (s, 3H), 4.18 (s, 3H), 5.13 (m, 2H), 5.80(s, 2H), 6.91 (s, 1H), 7.26 (s, 1H), 7.31 (d, J=3.6 Hz, 1H), 7.46 (d,J=3.6 Hz, 1H), 7.94 (d, J=9.6 Hz, 1H), 8.03 (d, J=9.6 Hz, 1H), 10.30 (s,1H)

Example 40 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-(6-chloro)-piperonyloxy-13-ethyl-10-methoxybenzo[g]quinoliziniumchloride (Compound No. 40)

The process of Example 1 was repeated except that 0.56 g of6-chloropiperonyl chloride was employed in place of dodecyl bromide togive 0.75 g of the titled compound as a brown crystal (m.p.: 105° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.70 (t, J=7.8 Hz, 3H), 3.38 (m, 4H), 3.96(s, 3H), 3.99 (s, 3H), 4.11 (s, 3H), 4.82 (m, 2H), 5.00 (m, 2H), 5.59(s, 2H), 6.95 (s, 1H), 7.26 (s, 1H), 7.42 (s, 1H), 7.51 (s, 1H), 7.95(d, J=9.3 Hz, 1H), 8.09 (d, J=9.3 Hz, 1H), 9.89 (s, 1H)

Example 41 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(2-methyl)propenoxybenzo[g]quinoliziniumchloride (Compound No. 41)

The process of Example 1 was repeated except that 0.25 g of3-chloro-2-methylpropene was employed in place of dodecyl bromide togive 0.46 g of the titled compound as a brown crystal (m.p.: 195° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.68 (t, J=7.8 Hz, 3H), 2.01 (s, 3H), 3.39(m, 4H), 3.96 (s, 3H), 4.00 (s, 3H), 4.08 (s, 3H), 5.05 (m, 4H), 5.40(m, 2H), 6.93 (s, 1H), 7.26 (s, 1H), 7.91 (d, J=9.3 Hz, 1H), 7.98 (d,J=9.3 Hz, 1H), 10.01 (s, 1H)

Example 42 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(4-trifluoromethoxy)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 42)

The process of Example 1 was repeated except that 0.69 g of4-trifluoromethoxy benzyl bromide was employed in place of dodecylbromide to give 0.49 g of the titled compound as a brown crystal (m.p.:103° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.63 (t, J=7.5 Hz, 3H), 3.25 (m, 2H), 3.46(m, 2H), 3.94 (s, 3H), 4.00 (s, 3H), 4.11 (s, 3H), 5.24 (m, 2H), 5.76(s, 2H), 6.84 (s, 1H), 7.24 (s, 1H), 7.25 (d, J=9.6 Hz, 2H), 7.29 (d,J=9.6 Hz, 2H), 7.93 (d, J=9.3 Hz, 1H), 7.96 (d, J=9.3 Hz, 1H), 10.54 (s,1H)

Example 43 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-9-(2-iodo)benzyloxy-10-methoxybenzo[g]quinoliziniumchloride (Compound No. 43)

The process of Example 1 was repeated except that 0.68 g of 2-iodobenzylchloride was employed in place of dodecyl bromide to give 0.50 g of thetitled compound as a brown crystal (m.p.: 110° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.60 (t, J=8.3 Hz, 3H), 3.35 (m, 2H), 3.50(m, 2H), 3.96 (s, 3H), 4.00 (s, 3H), 4.11 (s, 3H), 5.00 (m, 2H), 5.65(s, 2H), 6.94 (s, 1H), 7.07 (m, 2H), 7.47 (m, 2H), 7.96 (d, J=9.3 Hz,1H), 8.02 (d, J=9.3 Hz, 1H), 10.00 (s, 1H)

Example 44 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-[(3-trimethylsilyl)propen-2-yl]oxybenzo[g]quinoliziniumchloride (Compound No. 44)

The process of Example 1 was repeated except that 0.44 g of2-chloromethyl-3-trimethylsilyl-1-propene was employed in place ofdodecyl bromide to give 0.59 g of the titled compound as a brown crystal(m.p.: 195° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.63 (t, J=7.8 Hz, 3H), 3.32 (m, 2H), 3.41(m, 2H), 3.96 (s, 3H), 4.00 (s, 3H), 4.08 (s, 3H), 5.05 (m, 6H), 6.92(s, 1H), 7.26 (s, 1H), 7.90 (d, J=9.3 Hz, 1H), 7.98 (d, J=9.3 Hz, 1H),10.01 (s, 1H)

Example 45 Preparation of5,6-dihydro-2,3-methylenedioxybenzo[a]-9-dodecoxy-13-ethyl-10-methoxybenzo[g]quinoliziniumiodide (Compound No. 45)

10 G of5,6-dihydro-2,3-methylenedioxybenzo[a]-9,10-dimethoxy-13-ethylbenzo[g]quinoliziniumchloride was subjected to pyrolysis under nitrogen atmosphere at atemperature of 180° C. and then dissolved in methanol. Undissolvedby-products were filtered off and the residue was then purified bysilica gel column chromatography eluting with a mixed solvent ofmethanol/dichloromethane (10:1) to give 6 g of5,6-dihydro-2,3-methylenedioxybenzo[a]-13-ethyl-9-oxy-10-methoxy-benzo[g]quinoliziniumsalts as an orange crystal.

1 G of5,6-dihydro-2,3-methylenedioxybenzo[a]-13-ethyl-9-oxy-10-methoxy-benzo[g]quinolizinium,0.43 g of sodium iodide, and 0.39 g of potassium carbonate weredissolved in 10 ml of acetonitrile. After 0.71 g of dodecyl bromide wasadded thereto, the mixture was refluxed for 10 hours. Undissolvedby-products were filtered off and the filtrate was concentrated underreduced pressure to remove the solvent. The residue was then dissolvedin chloroform and washed with 10 ml of water. The organic solution wasdried over magnesium sulfate to remove water and concentrated. Theresidue was then purified by silica gel column chromatography elutingwith a mixed solvent of chloroform/methanol (15:1 ) to give 0.40 g ofthe titled compound as a brown crystal (m.p.: 175° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 0.88 (t, J=6.9 Hz, 3H), 1.28 (m, 12H), 1.53(m, 4H), 1.69 (t, J=7.2 Hz, 3H), 1.98 (m, 4H), 3.35 (m, 2H), 3.41 (m,2H), 4.41 (s, 3H), 4.50 (t, J=6.9 Hz, 2H), 5.10 (m, 2H), 6.12 (s, 2H),6.93 (s, 1H), 7.30 (s, 1H), 8.00 (d, J=9.3 Hz, 1H), 8.14 (d, J=9.3 Hz,1H), 10.01 (s, 1H)

Example 46 Preparation of5,6-dihydro-2,3-methylenedioxybenzo[a]-9-[(4-tert-butyl)benzyloxy]-13-ethyl-10-methoxybenzo[g]quinoliziniumiodide (Compound No. 46)

The process of Example 45 was repeated except that 0.65 g of4-(tert-butyl)benzyl bromide was employed in place of dodecyl bromide togive 0.82 g of the titled compound as a brown crystal (m.p.: 155° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.29 (s, 9H), 1.69 (t, J=7.2 Hz, 3H), 3.22(m, 2H), 3.40 (m, 2H), 4.11 (s, 3H), 4.98 (m, 2H), 5.53 (s, 2H), 6.15(s, 2H), 6.97 (s, 1H), 7.21 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.65 (d,J=8.1 Hz, 2H), 8.05 (d, J=9.3 Hz, 1H), 8.88 (d, J=9.3 Hz, 1H), 10.02 (s,1H)

Example 47 Preparation of5,6-dihydro-2,3-methylenedioxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,4,5,6-pentafluoro)benzyloxybenzo[g]-quinoliziniumiodide (Compound No. 47)

The process of Example 45 was repeated except that 0.75 g of2,3,4,5,6-pentafluorobenzyl bromide was employed in place of dodecylbromide to give 0.92 g of the titled compound as a brown crystal (m.p.:112° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.69 (t, J=7.8 Hz, 3H), 3.38 (m, 2H), 3.40(m, 2H), 4.10 (s, 3H), 5.06 (m, 2H), 5.86 (s, 2H), 6.12 (s, 2H), 6.94(s, 1H), 7.29 (s, 1H), 7.93 (d, J=9.3 Hz, 1H), 8.04 (d, J=9.3 Hz, 1H),10.10 (s, 1H)

Example 48 Preparation of5,6-dihydro-2,3-methylenedioxybenzo[a]-9-(4,5-dimethoxy-2-nitro)benzyloxy-13-ethyl-10-methoxybenzo[g]-quinoliziniumiodide (Compound No. 48)

The process of Example 45 was repeated except that 0.79 g of4,5-dimethoxy-2-nitrobenzyl bromide was employed in place of dodecylbromide to give 0.49 g of the titled compound as a brown crystal (m.p.:132° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.61 (t, J=7.2 Hz, 3H), 3.20 (m, 2H), 3.39(m, 2H), 3.98 (s, 3H), 4.01 (s, 3H), 4.22 (s, 3H), 5.18 (m, 2H), 5.79(s, 2H), 6.13 (s, 2H), 6.91 (s, 1H), 7.23 (s, 1H), 7.44 (s, 1H), 7.70(s, 1H), 7.90 (d, J=9.0 Hz, 1H), 8.00 (d, J=9.0 Hz, 1H), 10.31 (s, 1H)

Example 49 Preparation of5,6-dihydro-2,3-methylenedioxybenzo[a]-13-ethyl-10-methoxy-9-(4-methyl-3-nitro)benzyloxybenzo[g]quinoliziniumiodide (Compound No. 49)

The process of Example 45 was repeated except that 0.53 g of4-methyl-3-nitrobenzyl chloride was employed in place of dodecyl bromideto give 0.50 g of the titled compound as a brown crystal (m.p.: 115°C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.67 (t, J=6.9 Hz, 3H), 2.61 (s, 3H), 3.26(m, 2H), 3.35 (m, 2H), 4.14 (s, 3H), 5.01 (m, 2H), 5.78 (s, 2H), 6.13(s, 2H), 6.90 (s, 1H), 7.23 (s, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.92 (d,J=9.6 Hz, 1H), 8.00 (d, J=9.6 Hz, 1H), 8.24 (d, J=9.3 Hz, 1H), 8.35 (m,1H), 10.18 (s, 1H)

Example 50 Preparation of5,6-dihydro-2,3-methylenedioxybenzo[a]-13-ethyl-10-methoxy-9-(4-trifluoromethyl)benzyloxybenzo[g]quinoliziniumiodide (Compound No. 50)

The process of Example 45 was repeated except that 0.68 g of4-trifluoromethyl benzyl bromide was employed in place of dodecylbromide to give 0.75 g of the titled compound as a brown crystal (m.p.:142° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.67 (t, J=7.5 Hz, 3H), 3.24 (m, 2H), 3.37(m, 2H), 4.10 (s, 3H), 5.08 (m, 2H), 5.79 (s, 2H), 6.15 (s, 2H), 6.91(s, 1H), 7.26 (s, 1H), 7.64 (d, J=9.3 Hz, 2H), 7.86 (d, J=9.3 Hz, 2H),7.98 (d, J=7.8 Hz, 1H), 8.03 (d, J=7.8 Hz, 1H), 10.16 (s, 1H)

Example 51 Preparation of5,6-dihydro-2,3-methylenedioxybenzo[a]-13-ethyl-10-methoxy-9-(3-trifluoromethyl)benzyloxybenzo[g]quinoliziniumiodide (Compound No. 51)

The process of Example 45 was repeated except that 0.68 g of3-(trifluoromethyl)benzyl bromide was employed in place of dodecylbromide to give 0.53 g of the titled compound as a brown crystal (m.p.:134° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.67 (t, J=6.8 Hz, 3H), 3.34 (m, 2H), 3.38(m, 2H), 4.10 (s, 3H), 5.00 (m, 2H), 5.80 (s, 2H), 6.14 (s, 2H), 6.91(s, 1H), 7.26 (s, 1H), 7.62 (m, 3H), 7.92 (d, J=9.6 Hz, 1H), 8.00 (d,J=9.6 Hz, 1H), 8.17 (d, J=6.9 Hz, 1H), 10.14 (s, 1H)

Example 52 Preparation of5,6-dihydro-2,3-methylenedioxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,5,6-tetrafluoro-4-trifluoromethyl)benzyloxybenzo[g]quinoliziniumiodide (Compound No. 52)

The process of Example 45 was repeated except that 0.89 g of2,3,5,6-tetrafluoro-4-trifluoromethyl benzyl bromide was employed inplace of dodecyl bromide to give 0.99 g of the titled compound as abrown crystal (m.p.: 136° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.67 (t, J=7.5 Hz, 3H), 3.32 (m, 2H), 3.40(m, 2H), 4.07 (s, 3H), 5.10 (m, 2H), 5.94 (s, 2H), 6.11 (s, 2H), 6.92(s, 1H), 7.25 (s, 1H), 7.90 (d, J=9.3 Hz, 1H), 8.04 (d, J=9.3 Hz, 1H),10.18 (s, 1H)

Example 53 Preparation of5,6-dihydro-2,3-methylenedioxybenzo[a]-13-ethyl-10-methoxy-9-(4-phenyl)benzloxybenzo[g]quinoliziniumiodide (Compound No. 53)

The process of Example 45 was repeated except that 0.58 g of4-phenylbenzyl chloride was employed in place of dodecyl bromide to give0.69 g of the titled compound as a brown crystal (m.p.: 115° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.66 (t, J=7.5 Hz, 3H), 3.24 (m, 2H), 3.34(m, 2H), 4.13 (s, 3H), 5.04 (m, 2H), 5.71 (s, 2H), 6.17 (s, 2H), 6.90(s, 1H), 7.24 (s, 1H), 7.38 (d, J=7.2 Hz, 2H), 7.42 (d, J=7.5 Hz, 2H),7.46 (d, J=7.2 Hz, 2H), 7.58 (d, J=7.5 Hz, 2H), 7.86 (d, J=9.3 Hz, 1H),8.00 (d, J=9.3 Hz, 1H), 10.12 (s, 1H)

Example 54 Preparation of5,6-dihydro-2,3-methylenedioxybenzo[a]-9-(6-chloropyridinyl-3-yl)methoxy-13-ethyl-10-methoxybenzo[g]quinoliziniumiodide (Compound No. 54)

The process of Example 45 was repeated except that 0.46 g of3-chloromethyl-6-chloropyridine was employed in place of dodecyl bromideto give 0.44 g of the titled compound as a brown crystal (m.p.: 139°C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.68 (t, J=7.5 Hz, 3H), 3.26 (m, 2H), 3.38(m, 2H), 4.12 (s, 3H), 5.14 (m, 2H), 5.78 (s, 2H), 6.11 (s, 2H), 6.91(s, 1H), 7.26 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.90 (d, J=9.6 Hz, 1H),8.00 (d, J=9.6 Hz, 1H), 8.52 (m, 1H), 8.68 (m, 1H), 10.25 (s, 1H)

Example 55 Preparation of5,6-dihydro-2,3-diethoxybenzo[a]-9-[4-(tert-butyl)benzyloxy]-13-ethyl-10-methoxybenzo[g]quinoliziniumchloride (Compound No. 55)

To a solution of 10 g of5,6-dihydro-2,3-dihydroxybenzo[a]-13-ethyl-9-hydroxy-10-methoxybenzo[g]quinoliziniumchloride in 100 ml of acetonitrile 8.1 g of potassium carbonate and 9.1g of ethyl iodide. The mixture was refluxed for 5 hours. Undissolvedby-products were filtered off and the filtrate was concentrated underreduced pressure to remove the solvent. The residue was then dissolvedin chloroform and washed with 50 ml of water. The organic solution wasdried over magnesium sulfate to remove water, filtered, andconcentrated. The residue was then purified by silica gel columnchromatography eluting with a mixed solvent of methanol/dichloromethane(2:1) to give 8.5 g of5,6-dihydro-2,3-diethoxybenzo[a]-13-ethyl-9-hydroxy-10-methoxybenzo[g]quinoliziniumchloride as a light brown crystal.

To a solution of 1 g of5,6-dihydro-2,3-diethoxybenzo[a]-13-ethyl-9-hydroxy-10-methoxy-benzo[g]quinoliziniumchloride in 10 mg acetonitrile were added, 0.38 g of sodium iodide, and0.35 g of potassium carbonate. After 0.58 g of 4-(tert-butyl)benzylbromide was added thereto, the mixture was refluxed for 3 hours.Undissolved by-products were filtered off and the filtrate wasconcentrated under reduced pressure to remove the solvent. The residuewas then dissolved in chloroform and washed with 10 ml of water. Theorganic solution was dried over magnesium sulfate to remove water,filtered, and concentrated. The residue was then purified by silica gelcolumn chromatography eluting with a mixed solvent ofchloroform/methanol (15:1) to give 0.72 g of the titled compound as abrown crystal (m.p.: 132° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.29 (s, 9H), 1.67 (m, 9H), 3.24 (m, 2H),3.40 (m, 2H), 4.04 (m, 4H), 4.11 (s, 3H), 4.99 (m, 2H), 5.54 (s, 2H),6.94 (s, 1H), 7.23 (s, 1H), 7.40 (d, J=9.3 Hz, 2H), 7.66 (d, J=9.3 Hz,2H), 8.04 (d, J=9.3 Hz, 1H), 8.87 (d, J=9.3 Hz, 1H), 10.11 (s, 1H)

Example 56 Preparation of5,6-dihydro-2,3-diethoxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,4,5,6-pentafluoro)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 56)

The process of Example 55 was repeated except that 0.67 g of2,3,4,5,6-pentafluorobenzyl bromide was employed in place of4-(tert-butyl)benzyl bromide to give 0.82 g of the titled compound as abrown crystal (m.p.: 100° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.67 (m, 9H), 3.36 (m, 2H), 3.42 (m, 2H),4.01 (m, 4H), 4.08 (s, 3H), 5.06 (m, 2H), 5.86 (s, 2H), 6.93 (s, 1H),7.28 (s, 1H), 7.92 (d, J=9.3 Hz, 1H), 8.04 (d, J=9.3 Hz, 1H), 10.12 (s,1H)

Example 57 Preparation of5,6-dihydro-2,3-diethoxybenzo[a]-9-(2,3,5,6-tetrafluoro-4-trifluoromethyl)benzyloxy-13-ethyl-10-methoxy-benzo[g]-quinoliziniumchloride (Compound No. 57)

The process of Example 55 was repeated except that 0.80 g of2,3,5,6-tetrafluoro-4-trifluoromethyl benzyl bromide was employed inplace of 4-(tert-butyl)benzyl bromide to give 0.68 g of the titledcompound as a brown crystal (m.p.: 113° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.69 (m, 9H), 3.34 (m, 2H), 3.40 (m, 2H),3.96 (m, 4H), 4.07 (s, 3H), 5.12 (m, 2H), 5.96 (s, 2H), 6.92 (s, 1H),7.25 (s, 1H), 7.92 (d, 1H, J=9.6 Hz), 8.06 (d, 1H, J=9.6 Hz), 10.24 (s,1H)

Example 58 Preparation of5,6-dihydro-2,3-diethoxybenzo[a]-9-(6-chloropyridinyl-3-yl)methoxy-13-ethyl-10-methoxybenzo[g]-quinolizinium chloride (Compound No. 58)

The process of Example 55 was repeated except that 0.42 g of3-chloro-6-chloropyridine was employed in place of 4-(tert-butyl)benzylbromide to give 0.42 g of the titled compound as a brown crystal (m.p.:126° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.68 (m, 9H), 3.26 (m, 2H), 3.38 (m, 2H),4.01 (m, 4H), 4.12 (s, 3H), 5.11 (m, 2H), 5.78 (s, 2H), 6.91 (s, 1H),7.26 (s, 1H), 7.45 (d, J=9.3 Hz, 1H), 7.91 (d, J=9.6 Hz, 1H), 8.00 (d,J=9.6 Hz, 1H), 8.52 (m, 1H), 8.64 (m, 1H), 10.30 (s, 1H)

Example 59 Preparation of5,6-dihydro-2,3-dihydroxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,4,5,6-pentafluoro)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 59)

To a solution of 1 g of5,6-dihydro-2,3-dihydroxybenzo[a]-13-ethyl-9-hydroxy-10-methoxy-benzo[g]quinoliziniumchloride in 10 mg of acetonitrile were added 0.44 g of sodium iodide,and 0.41 g of potassium carbonate. After 0.77 g of2,3,4,5,6-pentafluorobenzyl bromide was added thereto, the reactionmixture was stirred for 24 hours in an ice bath. After pH was adjustedto neutral with an aqueous hydrochloric acid solution, undissolvedby-products were filtered off and the filtrate was concentrated underreduced pressure to remove the solvent. The residue was then dissolvedin chloroform and washed with 10 ml of water. The organic solution wasdried over magnesium sulfate to remove water filtered, and concentrated.The residue was then purified by silica gel column chromatographyeluting with a mixed solvent of chloroform/methanol (15:1) to give 0.34g of the titled compound as a brown crystal (m.p.: 82° C.).

¹ H-NMR (300 MHz, DMSO-d₆) δ: 1.47 (t, 3H), 3.12 (m, 2H), 3.34 (m, 2H),4.01 (s, 3H), 4.82 (m, 2H), 5.72 (s, 2H), 7.17 (s, 1H), 7.31 (s, 1H),8.19 (d, J=7.2 Hz, 1H), 8.22 (d, J=7.2 Hz, 1H), 9.95 (s, 1H)

Example 60 Preparation of5,6-dihydro-2,3-dihydroxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,5,6-tetrafluoro-4-trifluoromethyl)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 60)

The process of Example 59 was repeated except that 0.92 g of2,3,5,6-tetrafluoro-4-trifluoromethyl benzyl bromide was employed inplace of 2,3,4,5,6-pentafluorobenzyl bromide to give 0.25 g of thetitled compound as a brown crystal (m.p.: 88° C.).

¹ H-NMR (300 MHz, DMSO-d₆) δ: 1.48 (t, J=6.3 Hz, 3H), 3.18 (m, 2H), 3.37(m, 2H), 4.07 (s, 3H), 4.91 (m, 2H), 5.77 (s, 2H), 6.84 (s, 1H), 7.11(s, 1H), 8.01 (d, J=9.3 Hz, 1H), 8.07 (d, J=9.3 Hz, 1H), 9.99 (s, 1H)

Example 61 Preparation of5,6-dihydro-2,3-diethoxybenzo[a]-9-dodecoxy-10-ethoxy-13-ethylbenzo[g]quinoliziniumchloride (Compound No. 61)

To a solution of 10 g of5,6-dihydro-2,3-methylenedioxybenzo[a]-9,10-dimethoxy-13-ethyl-benzo[g]quinoliziniumchloride in 100 mg of dichloromethane was suspended 30 g of aluminumchloride and the mixture was stirred for 1 hour. The reaction mixturewas concentrated under reduced pressure to remove the solvent. A 15%aqueous hydrochloric acid solution was added to the mixture and theprecipitate produced was filtered, washed with water, and dried to give7.5 g of5,6-dihydro-2,3-dihydroxybenzo[a]-9,10-dihydroxy-13-ethylbenzo[g]quinoliziniumchloride as dark brown crystal.

To a solution of 10 g of5,6-dihydro-2,3-dihydroxybenzo[a]-9,10-dihydroxy-13-ethylbenzo-[g]quinoliziniumchloride in 100 ml of acetonitrile were added 12.1 g of potassiumcarbonate and 14.3 g of ethyl iodide. The mixture was refluxed for 5hours. Undissolved by-products were filtered off and the filtrate wasconcentrated under reduced pressure to remove the solvent. The residuewas then dissolved in chloroform and washed with 50 ml of water. Theorganic solution was dried over magnesium sulfate to remove water,filterated, and concentrated. The residue was then purified by silicagel column chromatography eluting with a mixed solvent ofmethanol/dichloro-methane (2:1) to give 7.8 g of5,6-dihydro-2,3-diethoxybenzo[a]-10-ethoxy-13-ethyl-9-hydroxybenzo[g]quinoliziniumchloride as a light brown crystal.

To a solution of 1 g of5,6-dihydro-2,3-diethoxybenzo[a]-10-ethoxy-13-ethyl-9-hydroxy-benzo[g]quinoliziniumchloride in 10 mg of acetonitrile were added 0.37 g of sodium iodide and0.34 g of potassium carbonate. After 0.62 g of dodecyl bromide was thenadded thereto, the mixture was refluxed for 10 hours. Undissolvedby-products were filtered off and the filtrate was concentrated underreduced pressure to remove the solvent. The residue was then dissolvedin chloroform and washed with 10 ml of water. The organic solution wasdried over magnesium sulfate to remove water, filtered, andconcentrated. The residue was then purified by silica gel columnchromatography eluting with a mixed solvent of chloroform/methanol(15:1) to give 0.37 g of the titled compound as a brown crystal (m.p.:174° C.).

¹ H-NMR (300MHz, CDCl₃) δ: 0.87 (t, J=6.9 Hz, 3H), 1.24 (m, 12H), 1.50(m, 4H), 1.68 (m, 12H), 1.98 (m, 4H), 3.34 (m, 2H), 3.48 (m, 2H), 4.01(m, 8H), 4.52 (t, J=6.9 Hz, 2H), 5.20 (m, 2H), 6.93 (s, 1H), 7.30 (s,1H), 8.04 (d, J=9.3 Hz, 1H), 8.13 (d, J=9.3 Hz, 2H), 10.07 (s, 1H)

Example 62 Preparation of5,6-dihydro-2,3-diethoxybenzo[a]-10-ethoxy-13-ethyl-9-(4-trifluoromethyl)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 62)

The process of Example 61 was repeated except that 0.59 g of4-trifluoromethyl benzyl bromide was employed in place of dodecylbromide to give 0.83 g of the titled compound as a brown crystal (m.p.:142° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.69 (m, 12H), 3.26 (m, 2H), 3.34 (m, 2H),4.00 (m, 12H), 5.08 (m, 2H), 5.80 (s, 2H), 6.93 (s, 1H), 7.25 (s, 1H),7.68 (d, J=9.6 Hz, 2H), 7.84 (d, J=9.6 Hz, 2H), 7.96 (d, J=7.4 Hz, 1H),8.04 (d, J=7.4 Hz, 1H), 10.21 (s, 1H)

Example 63 Preparation of5,6-dihydro-2,3-diethoxybenzo[a]-10-ethoxy-13-ethyl-9-(3-trifluoromethyl)benzyloxyenzo[g]quinoliziniumchloride (Compound No. 63)

The process of Example 61 was repeated except that 0.59 g of3-trifluoromethylbenzyl bromide was employed in place of dodecyl bromideto give 0.58 g of the titled compound as a brown crystal (m.p.: 127°C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.70 (m, 12H), 3.32 (m, 2H), 3.38 (m, 2H),4.10 (m, 12H), 5.00 (m, 2H), 5.85 (s, 2H), 6.92 (s, 1H), 7.26 (s, 1H),7.62 (m, 3H), 7.92 (d, J=9.6 Hz, 1H), 8.00 (d, J=9.6 Hz, 1H), 8.18 (d,J=6.9 Hz, 1H), 10.17 (s, 1H)

Example 64 Preparation of5,6-dihydro-2,3-diethoxybenzo[a]-10-ethoxy-13-ethyl-9-(2,3,5,6-tetrafluoro-4-trifluoromethyl)-benzyloxybenzo[g]quinolizinium chloride (Compound No. 64)

The process of Example 61 was repeated except that 0.77 g of2,3,5,6-tetrafluoro-4-trifluoromethyl benzyl bromide was employed inplace of dodecyl bromide to give 0.68 g of the titled compound as abrown crystal (m.p.: 110° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.64 (m, 12H), 3.30 (m, 2H), 3.40 (m, 2H),4.07 (m, 12H), 5.10 (m, 2H), 5.98 (s, 2H), 6.92 (s, 1H), 7.25 (s, 1H),7.92 (d, J=9.6 Hz, 1H), 8.06 (d, J=9.6 Hz, 1H), 10.20 (s, 1H)

Example 65 Preparation of5,6-dihydro-2,3-diethoxybenzo[a]-9-(6-chloropyridine-3-yl)methoxy-10-ethoxy-13-ethylbenzo[g]-quinoliziniumchloride (Compound No. 65)

The process of Example 61 was repeated except that 0.4 g of3-chloromethyl-6-chloropyridine was employed in place of dodecyl bromideto give 0.37 g of the titled compound as a brown crystal (m.p.: 136°C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.68 (m, 12H), 3.24 (m, 2H), 3.38 (m, 2H),4.12 (m, 12H), 5.13 (m, 2H), 5.78 (s, 2H), 6.90 (s, 1H), 7.26 (s, 1H),7.41 (d, J=9.3 Hz, 1H), 7.92 (d, J=9.6 Hz, 1H), 8.00 (d, J=9.6 Hz, 1H),8.54 (m, 1H), 8.66 (m, 1H), 10.23 (s, 1H)

Example 66 Preparation of5,6-dihydro-2,3-dipropoxybenzo[a]-9-[4-(tert-butyl)benzyloxy]-13-ethyl-10-propoxybenzo[g]quinoliziniumchloride (Compound No. 66)

To a solution of 10 g of 5,6dihydro-2,3-dihydroxybenzo[a]-9,10-dihydroxy-13-ethylbenzo-[g]quinoliziniumchloride in 100 ml of acetonitrile 12.1 g of potassium carbonate and15.6 g of propyl iodide. The mixture was refluxed for 8 hours.Undissolved by-products were filtered off and the filtrate wasconcentrated under reduced pressure to remove the solvent. The residuewas then dissolved in chloroform and washed with 50 ml of water. Theorganic solution was dried over magnesium sulfate to remove water,filtered and concentrated. The residue was then purified by silica gelcolumn chromatography eluting with a mixed solvent ofmethanol/dichloromethane (2:1) to give 7.8 g of5,6-dihydro-2,3-dipropoxybenzo[a]-13-ethyl-9-hydroxy-10-propoxybenzo[g]quinoliziniumchloride as a light brown crystal.

To a solution of 1 g of5,6-dihydro-2,3-dipropoxybenzo[a]-13-ethyl-9-hydroxy-10-propoxy-benzo[g]quinoliziniumchloride in 10 mg of acetonitrile were added 0.34 g of sodium iodide and0.31 g of potassium carbonate. After 0.51 g of 4-(tert-butyl)benzylbromide was added thereto, the mixture was refluxed for 5 hours.Undissolved by-products were filtered off and the filtrate wasconcentrated under reduced pressure to remove the solvent. The residuewas then dissolved in chloroform and washed with 10 ml of water. Thesolution was dried over magnesium sulfate to remove water, filtered, andconcentrated. The residue was then purified by silica gel columnchromatography eluting with a mixed solvent of chloroform/methanol(15:1) to give 0.68 g of the titled compound as a brown crystal (m.p.:133° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.29 (s, 9H), 1.48 (m, 9H), 1.72 (m, 6H),3.24 (m, 2H), 3.45 (m, 2H), 4.18 (m, 6H), 4.99 (m, 2H), 5.53 (s, 2H),6.95 (s, 1H), 7.23 (s, 1H), 7.44 (d, J=9.6 Hz, 2H), 7.66 (d, J=9.6 Hz,2H), 8.07 (d, J=9.3 Hz, 1H), 8.87 (d, J=9.3 Hz, 1H), 10.05 (s, 1H)

Example 67 Preparation of5,6-dihydro-2,3-dipropoxybenzo[a]-13-ethyl-9-(2,3,4,5,6-pentafluoro)benzyloxy-10-propoxybenzo[g]quinoliziniumchloride (Compound No. 67)

The process of Example 66 was repeated except that 0.59 g of2,3,4,5,6-pentafluorobenzyl bromide was employed in place of4-(tert-butyl)benzyl bromide to give 0.90 g of the titled compound as abrown crystal (m.p.: 122° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.49 (m, 9H), 1.59 (m, 6H), 3.36 (m, 2H),3.40 (m, 2H), 4.15 (m 6H), 5.06 (m, 2H), 5.84 (s, 2H), 6.93 (s, 1H),7.28 (s, 1H), 7.91 (d, J=9.6 Hz, 1H), 8.05 (d, J=9.6 Hz, 1H), 10.08 (s,1H)

Example 68 Preparation of5,6-dihydro-2,3-dipropoxybenzo[a]-13-ethyl-10-propoxy-9-(4-trifluoromethyl)benzyloxybenzo[g]quinoliziniumchloride (Compound No. 68)

The process of Example 66 was repeated except that 0.54 g of4-trifluoromethylbenzyl bromide was employed in place of4-(tert-butyl)benzyl bromide to give 0.95 g of the titled compound as abrown crystal (m.p.: 151° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.50 (m, 9H), 1.69 (m, 6H), 3.24 (m, 2H),3.36 (m, 2H), 4.10 (m, 6H), 5.08 (m, 2H), 5.79 (s, 2H), 6.91 (s, 1H),7.26 (s, 1H), 7.64 (d, J=9.3 Hz, 2H), 7.86 (d, J=9.3 Hz, 2H), 7.96 (d,J=7.8 Hz, 1H), 8.02 (d, J=7.8 Hz, 1H), 10.21 (s, 1H)

Example 69 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-[4-(tert-butyl)-benzyloxy]-13-ethyl-10-methoxybenzo[g]quinoliziniumbisulfate (Compound No. 69)

1 G of 8-acetonylated5,6-dihydro-2,3-dimethoxybenzo[a]-9-[4-(tert-butyl)benzyloxy]-13-ethyl-10-methoxybenzo[g]quinoliziniumchloride was introduced into 10 ml of 1.0M sulfuric acid. After thesolution was stirred at room temperature for 2 hour, the precipitateproduced was filtered, washed with 5 ml of water and then dried overoven to give 0.58 g of the titled compound as a brown crystal (m.p.:123° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.30 (s, 9H), 1.70 (t, J=7.2 Hz, 3H), 3.24(m, 2H), 3.40 (m, 2H), 3.92 (s, 3H), 3.99 (s, 3H), 4.14 (s, 3H), 4.98(m, 2H), 5.56 (s, 2H), 6.97 (s, 1H), 7.25 (s, 1H), 7.46 (d, J=8.1 Hz,2H), 7.62 (d, J=8.1 Hz, 2H), 8.02 (d, J=9.3 Hz, 1H), 8.87 (d, J=9.3 Hz,1H), 9.98 (s, 1H)

Example 70 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,4,5,6-pentafluoro)benzyloxybenzo[g]quinoliziniumacetate (Compound No. 70)

1 G of 8-acetonylated5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,4,5,6-pentafluorobenzyloxybenzo[g]quinoliziniumchloride was introduced into 10 ml of glacial acetic acid and themixture was stirred at at room temperature for 5 hours. The precipitateproduced was filtered, washed with 10 ml of ether and then dried overoven to give 0.75 g of the titled compound as a brown crystal (m.p.:108° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.62 (t, J=7.8 Hz, 3H), 3.35 (m, 2H), 3.29(m, 2H), 3.96 (s, 1H), 4.08 (s, 3H), 4.14 (s, 1H), 5.08 (m, 2H), 5.86(s, 2H), 7.00 (s, 1H), 7.23 (s, 1H), 7.39 (d, J=9.3 Hz, 1H), 8.04 (d,J=9.3 Hz, 1H), 9.98 (s, 1H)

Example 71 Preparation of5,6-dihydro-2,3-dimethoxybenzo[a]-9-(6-chloropyridine-3-yl)methoxy-13-ethyl-10-methoxybenzo-[g]quinoliziniumnitrate (Compound No. 71)

1 G of 8-acetonylated5,6-dihydro-2,3-dimethoxybenzo[a]-9-(6-chloropyridine-3-yl)methoxy-13-ethyl-10-methoxybenzo[g]quinoliziniumchloride was introduced into 10 ml of 1.3M nitric acid and the mixturewas stirred at room temperature for 2 hour. The precipitate produced wasfiltered, washed with 5 ml of water and then dried over oven to give0.82 g of the titled compound as a brown crystal (m.p.: 127° C.).

¹ H-NMR (300 MHz, CDCl₃) δ: 1.62 (t, J=7.5 Hz, 3H), 3.22 (m, 2H), 3.32(m, 2H), 3.93 (s, 3H), 4.00 (s, 3H), 4.14 (s, 3H), 5.10 (m, 2H), 5.78(s, 2H), 6.90 (s, 1H), 7.26 (s, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.92 (d,J=9.3 Hz, 1H), 8.00 (d, J=9.3 Hz, 1H), 8.54 (m, 1H), 8.68 (m, 1H), 10.15(s, 1H)

Example 72 Inhibiting effect of 5,6-dihydrodibenzo[a,g]quinoliziniumsalts on sterol 14-reductase in microsome state

20 Male Sprague-Dawley rats weighing from 150 to 250 g have been fed for7 days with a diet containing 0.1% (w/w) Lovastatin and 5% (w/w)Cholestyramine. The animals were fasted for 12 hours before excisingliver tissues and then sacrificed by decapitation at midnight. Anaqueous solution containing 0.25M of sucrose was injected into thehepatic portal vein to remove all the blood within the liver, and then,the liver was excised. The liver was homogenated with two volumes ofbuffer solution A (0.1M potassium phosphate, 1 mM reduced glutathione,0.5 mM EDTA, 20% (v/v) glycerol, pH 7.4) by repeating pestles over 10times and then, centrifuged with 900×g for 5 minutes to give asupernatant. The supernatant was centrifuged with 12,000×g for 20minutes. The supernatant obtained was ultracentrifuged with 105,000×gfor 90 minutes to give a microsome which was used as an enzyme source ofsterol 14-reductase. Assay for sterol 14-reductase was carried out asfollows:

60 mmol of 4,4-dimethyl-5α-cholesta-7,14-dien-3β-ol and5,6-dihydrodibenzo-[a,g]quinolizinium salts (compound no. 2) dissolvedin DMSO were added to an assay mixture (total volume 1.0 ml) containing2 mg of the microsomal protein, 2 mM of NADPH and 25 mg of glucose plus20 units of glucose oxidase with preincubations under nitrogen at 37° C.for 4 min. unless otherwise specified to establish anaerobic condition.Buffer A (0.1M potassium phosphate buffer, pH 7.4, including 1 mMreduced glutathione, 0.5 mM EDTA, and 20% (v/v) glycerol) used forincubation had been equilibrated with nitrogen, and nitrogen wasexchanged for air in all sealed reaction flasks prior to the start ofincubations. Incubation of the complete mixture was carried outanaerobically in sealed flasks for 10 min at 37° C. unless otherwiseindicated. Incubations were terminated by the addition of 1 ml ofethanolic KOH followed by heating under reflux for 10 min. Sterols wereextracted four times with 4 ml of petroleum ether, and the solvent wasevaporated to dryness under a nitrogen stream. The resulting residue wasdissolved in 200-500 μl of n-hexane for quantification by GLC at highsensitive attenuation. The activity of sterol 14-reductase wasdetermined with the amount of the substrate wherein the double bonds of14-carbon were reduced (for the amount reduced by 1 mg of the microsomeprotein for 1 minute). When the level of compound no. 2 added to thereaction system was 0.1 to 0.3 μM, 50% of inhibition of the enzymaticactivity was observed.

Example 73 Effect of 5,6-dihydrodibenzo[a,g]quinolizinium salts oncholesterol biosynthesis ratio in CHO cells

Chinese hamster ovary cells (CHO cell) were passage-cultivated on theflat plates. When colonies reached at 70 to 80% of area based on thetotal culture area, culture medium was replaced with a fresh medium andthis was then used as samples for determining sterol 14-reductaseactivity and the cholesterol biosynthesis ratio.

Cholesterol biosynthesis ratio was determined by the Boogaard method[See, Biochem. J. 1987, 241, 345-51] with some modification. To thethree dishes (diameter: 60 nm) containing the above CHO cells, thecompound obtained from Example 2 were added and the mixture was thenincubated for 30 minutes. After adding each 0.5 μCi of ¹⁴ C-Mevalonateinto the medium, incubation was continued for 2 hours. Culture mediumwas removed from the vessel, and the mixture was then washed 3 timeswith PBS at 4° C. The cells were scratched and collected in about 1.0 mlof PBS, and then subjected to centrifugation at 10,000 rpm for 5 min. Inorder to determine cholesterol having radioactivity, the cellprecipitates were first floated with 0.1N NaOH. After quantifyingproteins in the floats, the floated material were taken so as to containa suitable amount of proteins. The total volume was adjusted to 1.0 mlwith the buffer solution A and added 1.0 ml of 25% ethanolic KOHsolution thereto to proceed saponification reaction at 80° C. for 30minutes. After dissolving unsaponicated sterols into n-hexane, they wereseparated by a thin layer liquid chromatography. The composition of thedeveloping solvents was ethyl acetate and benzene at 95:5 ratio andcholesterol was developed as the internal standard for 50 minutes. Bandsin the cholesterol-developed peak region were collected and put into aradioactive vial, and then 10 ml of scintillation cocktail solution wereadded thereto. The radioactivity strength of each sample was determinedby a liquid scintillation counter (LSC) to give the cholesterolbiosynthetic ratio. 50% of inhibitory effect was observed at the 0.1 to0.3 μM concentration of 5,6-dihydrodibenzo[a,g]quinolizinium salts(compound no. 2).

Example 74 Effect of 5,6-dihydrodibenzo[a,g]quinolizinium salts oncholesterol biosynthesis in cultured human liver cell line (HepG2 cells)

Cultured human liver HepG2 cell line was grown on RPMI (Rosewell parkMemorial Institute) 1640 culture medium containing 10% PBS until 60% ofmonolayer are formed in a 60 mm culture dish. After replacing the mediumwith 3 ml of a fresh culture medium containing 10% (v/v) LPDS (Fetalcalf lipoprotein-deficient serum), the cells were further grown for 48hours until 90% of cultivation degree appear The culture medium wasremoved and the cell was then washed with PBS. 2 ml of culture mediumcontaining compound no. 2 (final concentration 100 μM) and AY-9944(final concentration 1 μM) were added thereto. Then, the medium wascultivated at 37° C. for 1 hour under the condition of 95% air/5%carbonic acid gas. AY-9944 which is an inhibitor for sterol 7-reductasewas used as a control drug for assuring the present experimentalprocedure on the inhibition of cholesterol biosynthesis. Thereafter, 3μCi of [1,2-¹⁴ C]acetate (72 mCi/mmol) were added thereto. Thecultivation was continued for 2 hours so that the isotope is introducedinto the cell and used as a precursor for sterol to be synthesized.Then, the culture medium was completely removed and washed with PBStwice and the cells were collected by scratching. 10 μg of cholesterol,10 μg of lanosterol and [³ H]cholesterol (30,000 dpm) were addedthereto, and saponification reaction was carried out at 70° C. for anhour by adding 7.5% of methanolic KOH solution. Unsaponified sterol wasremoved by extracting them three times with 3 ml of petroleum ether anddried with nitrogen purging. The dried samples were redissolved in 200μl of chloroform. An aliquot of the samples was loaded onto Silicagel60F thin layer plate and then separated using ethyl acetate/hexane 25/75(v/v) as the developing solvent. The thin layer film was developed byexposure to Amersham Hyperfilm at -70° C. for 7 days. Cholesterol bandwere confirmed by comparing the band appeared in the film and thatappeared in the iodine-stained thin layer. After scratching thecholesterol band, it was quantified by a liquid scintillation counter.

Example 75 In vivo effect of 5,6-dihydrodibenzo[a,g]quinolizinium saltson cholesterol biosynthesis in Syrian Golden Hamster

Male Syrian Golden Hamsters weighing 90˜110 g distributed from SamyukAnimal Laboratory, Seoul, Korea were bred under the followingconditions: they were maintained under reverse light cycle (light cycle:from 6 P.M to 6 A.M; dark cycle: from 6 A.M. to 6 P.M.). The food andwater were supplied at 10 A.M. The commercially available standardrodent chows were used. The hamsters were divided into 6 or 7 animalsper group. The animals were fasted for 12 hours before administratingthe drug. Then, 5,6-dihydrodibenzo[a,g]quinolizinium salts (compound no.2) dissolved in a 0.25% methyl cellulose solution was administeredorally for 14 days at the indicated time per a day. After fastinganimals for 24 hours from the last administration, blood was extractedusing a cardiac puncture and plasma was then isolated. Plasma lipids,i.e., total cholesterol, LDL-cholesterol, HDL-cholesterol andtriglyceride values were analyzed using Automatic Analyzer (Hitachi7150).

Example 76 Preparation of pharmaceutically available tablets of5,6-dihydrodibenzo[a,g]quinolizinium salts

The raw drug materials corresponding to an amount of 10,000 tablets wereweighted and passed into 20 mesh sieve and the mixture was then blendedfor 10 minutes. The mixture was transferred to a compressor and wastableted under suitable pressure so as to give average weight of 200 mgper tablet.

    ______________________________________                                        Component               amount                                                ______________________________________                                        1) Composition of the raw drug materials per tablet (200 mg)                        Compound No. 2        10 mg                                               Calcium carboxymethyl cellulose 5 mg                                          Lactose #100 (100 mesh) 147.5 mg                                              Hydroxypropyl cellulose 5 mg                                                  Ludipress (BASF AG) 30 mg                                                     Magnesium stearate 2.5 mg                                                   2) Composition of the raw drug materials per tablet (200 mg)                        Compound No. 2        10 mg                                               Calcium carboxymethyl cellulose 5 mg                                          Lactose #100 (100 mesh) 147.5 mg                                              Hydroxypropyl cellulose 5 mg                                                  Kollidon VA64 (BASF AG) 30 mg                                                 Magnesium stearate 2.5 mg                                                   3) Composition of the raw drug materials per tablet (200 mg)                        Compound No. 3        5 mg                                                Calcium carboxymethyl cellulose 5 mg                                          Lactose #100 (100 mesh) 152.5 mg                                              Hydroxypropyl cellulose 5 mg                                                  Ludipress (BASF AG) 30 mg                                                     Magnesium stearate 2.5 mg                                                   4) Composition of the raw drug materials per tablet (200 mg)                        Compound No. 3        5 mg                                                Calcium carboxymethyl cellulose 5 mg                                          Lactose #100 (100 mesh) 152.5 mg                                              Hydroxypropyl cellulose 5 mg                                                  Kollidon VA64 (BASF AG) 30 mg                                                 Magnesium stearate 2.5 mg                                                   5) Composition of the raw drug materials per tablet (200 mg)                        Compound No. 68       2 mg                                                Calcium carboxymethyl cellulose 5 mg                                          Lactose #100 (100 mesh) 155.5 mg                                              Hydroxypropyl cellulose 5 mg                                                  Ludipress (BASF AG) 30 mg                                                     Magnesium stearate 2.5 mg                                                   6) Composition of the raw drug materials per tablet (200 mg)                        Compound No. 68       2 mg                                                Calcium carboxymethyl cellulose 5 mg                                          Lactose #100 (100 mesh) 155.5 mg                                              Hydroxypropyl cellulose 5 mg                                                  Kollidon VA64 (BASF AG) 30 mg                                                 Magnesium stearate 2.5 mg                                                   ______________________________________                                    

INDUSTRIAL APPLICABILITY

The compounds of formula (I) can effectively inhibit sterol 14-reductasewhich is involved in the distal pathway of cholesterol biosynthesis, andthus, are especially effective in treating hypercholesterolemia.

The compounds of formula (I) above have the activities to decrease totalcholesterol, LDL-cholesterol, and triglyceride levels and at the sametime, to decrease glucose level in an animal test. Therefore, they areeffective in diabetic hypercholesterolaemia and hyperlipidaemia.

Table 3 represents the relative activity for sterol 14-reductase of thecompound of formula (I) as set forth in Table 1. Among the compounds ofTable 1, Compound Nos. 2, 3, 9 and 68 markedly inhibited the cholesterolbiosynthesis in human HepG2 cell line compared with AY9944 which is acomparative drug. In the animal test with Syrian Golden Hamster,Compound Nos. 2, 3, 9 and 68 have markedly decreased total cholesterol,LDL-cholesterol, and triglyceride levels compared with lovastatin whichis a commercially available comparative cholesterol-lowering agent.

                  TABLE 3                                                         ______________________________________                                        Relative In Vitro activity for the compound of formula (I)                      Comp.     Enzyme   Comp.  Enzyme Comp.  Enzyme                                No. Activity No. Activity No. Activity                                      ______________________________________                                        1       +++      25       +      49     ++                                      2 +++ 26 + 50 ++                                                              3 +++ 27 + 51 ++                                                              4 ++ 28 + 52 ++                                                               5 +++ 29 ++ 53 ++                                                             6 +++ 30 + 54 ++                                                              7 ++ 31 + 55 +++                                                              8 + 32 + 56 +++                                                               9 +++ 33 + 57 +++                                                             10 ++ 34 ++ 58 ++                                                             11 +++ 35 + 59 ++                                                             12 + 36 ++ 60 +++                                                             13 +++ 37 + 61 +++                                                            14 + 38 ++ 62 ++                                                              15 + 39 ++ 63 ++                                                              16 +++ 40 + 64 ++                                                             17 +++ 41 + 65 ++                                                             18 ++ 42 ++ 66 ++                                                             19 ++ 43 ++ 67 ++                                                             20 ++ 44 + 68 +++                                                             21 + 45 ++ 69 ++                                                              22 + 46 +++ 70 ++                                                             23 ++ 47 +++ 71 ++                                                            24 + 48 +++                                                                 ______________________________________                                         +: 100 μM or more of IC.sub.50 value                                       ++: 10-100 μM of IC.sub.50 value                                           +++: 1 μM or below of IC.sub.50 value                                 

                  TABLE 4                                                         ______________________________________                                        In vivo activity result for Comp. Nos. 2, 3, 9, and 68                                           Total   HDL    LDL                                           Group  cholesterol cholesterol cholesterol Triglyceride                       No. n (mg/dl) (mg/dl) (mg/dl) (mg/dl)                                       ______________________________________                                        normal diet                                                                            5     130.8 ± 14                                                                           59.8 ± 7                                                                          37.0 ± 4                                                                          79.4 ± 13                             control                                                                       normal diet + 5 107.8 ± 9 67.0 ± 3 29.1 ± 2 55.5 ± 7                                                    lovastatin  (-17.6%) (+11.2%)                                                (-21.4%) (-30.1%)                        6.0 mg/kg/day                                                                 normal diet + 5 115.8 ± 8 66.6 ± 7 31.0 ± 3 67.8 ± 8                                                    comp. 2  (-11.5%) (+11.4%)                                                   (-16.0%) (-14.6%)                        0.3 mg/kg/day                                                                 normal diet + 5 89.0 ± 7 63.0 ± 3.0 18.8 ± 2 49.2 ± 6                                                   Comp. 3  (-23.5%) (+5.4%)                                                    (-49.2%) (-38.0%)                        0.3 mg/kg/day                                                                 normal diet + 5 82.4 ± 7 56.2 ± 3.0 20.2 ± 2 44.8 ± 5.5                                                 Comp. 9  (-37.0%) (-6.0%)                                                    (-45.4%) (-43.6%)                        0.3 mg/kg/day                                                                 normal diet + 5 87.4 ± 6 58.6 ± 3 21.8 ± 3 45.2 ± 7                                                     Comp. 68  (-33.1%) (-2.0%)                                                   (-41.1%) (-43.1%)                        0.3 mg/kg/day                                                               ______________________________________                                    

Meanwhile, the toxicity of the compounds of the present invention wasinvestigated as follows: i.e., the compounds were suspended intopropylene glycol and then orally administered into each of 5 male andfemale SD rats at the age of 5-weeks that were fasted for 12 hours.Under the usual breeding conditions, general symptoms, weight change andlethal case of the above rats were monitored for two weeks. At the doseover 2,000 mg/kg of the compound nos. 2, 3, 9 and 68, general symptomsand the body weight change of the animals were normal and the lethalcase was not observed. The toxicity data for the representativecompounds (Compound No. 2, 3, 9 and 68) is set forth in Table 5.

                  TABLE 5                                                         ______________________________________                                                 Acute Toxicity (mg/kg)                                                                  administratio                                                Comp. No. animal n route sex LD.sub.50                                      ______________________________________                                        Comp. 2    rats    oral        male  >2,000                                        female >2,000                                                              Comp. 3 rats oral male >2,000                                                    female >2,000                                                              Comp. 9 rats oral male >2,500                                                    female >2,000                                                              Comp. 68 rats oral male >3,000                                                   female >3,000                                                            ______________________________________                                    

As evident from the above descriptions, the compound of formula (I)inhibits sterol 14-reductase which is an enzyme in the distal stage ofthe cholesterol biosynthesis, thereby being effective in treatment ofhypercholesterolemia and hyperlipidaemia and safe in an aspect oftoxicity.

We claim:
 1. A 5,6-dihydrodibenzo[a,g]quinolizinium derivativerepresented by formula (I), one or more salt of the derivative or amixture thereof: ##STR78## wherein, R¹ and R², which may be the same ordifferent from each other, represent a hydroxy group or an alkoxy grouphaving 1 to 4 carbons or R¹ and R² together represent a methylenedioxygroup;R³ represents a hydroxy group or an alkoxy group having 1 to 4carbons; R⁴ represents an alkyl group having 2 to 8 carbons, or analkenyl group having 3 to 8 carbons; X represents an inorganic acid ion,an organic acid ion, or a halide; Z represents an alkyl group having 5to 12 carbons, or an alkenyl group having 4 to 6 carbons, aN-benzotriazolyl group, a quinolinyl group, a furyl group, a substitutedfuryl group, or a group represented by the formula: ##STR79## whereinZ¹, Z², Z³, Z⁴ and Z⁵, which may be the same or different from eachother, represent a hydrogen atom, halogen, an alkyl group having 1 to 5carbons, a trifluoromethyl group, a phenyl group, a substituted phenylgroup, a nitro group, an alkoxy group having 1 to 4 carbons, amethylenedioxy group, a trifluoromethoxy group, a hydroxy group, abenzyloxy group, a phenoxy group, a vinyl group, a benzenesulfonylmethylgroup or a methoxycarbonyl group; and A and B, which may be the same ordifferent from each other, represent carbon or nitrogen.
 2. Theinvention of claim 1, wherein Z represents a group having the followingchemical formula ##STR80## wherein Z¹, Z², Z³, Z⁴ and Z⁵ which may bethe same or different from each other, represent a hydrogen atom,halogen, an alkyl group having 1 to 5 carbons, a trifluoromethyl group,a phenyl group, a substituted phenyl group, nitro, an alkoxy grouphaving 1 to 4 carbons, a methylenedioxy group, a trifluoromethoxy group,a hydroxy group, a benzyloxy group, a phenoxy group, a vinyl group, abenzenesulfonylmethyl group or a methoxycarbonyl group; andA and B whichmay be the same or different from each other, represent carbon ornitrogen; and X represents inorganic acid ion, organic acid ion orhalide.
 3. The invention of claim 1, wherein R⁴ is ethyl group.
 4. Theinvention of claim 1, wherein R¹ is a methoxy group, R² is a methoxygroup, R³ is a methoxy group, R⁴ is an ethyl group, X is a chloride, andZ represents 4-(tert-butyl)phenyl.
 5. The invention of claim 1, whereinR¹ is a methoxy group, R² is a methoxy group, R³ is a methoxy group, R⁴is an ethyl group, X is a chloride, and Z represents2,3,4,5,6-pentafluorophenyl.
 6. The invention of claim 1, wherein R¹ isa methoxy group, R² is a methoxy group, R³ is a methoxy group, R⁴ is anethyl group, X is a chloride, and Z represents 4-trifluoromethylphenyl.7. The invention of claim 1, wherein R¹ and R² are a methylenedioxygroup, R³ is a methoxy group, R⁴ is an ethyl group, X is an iodide, andZ represents 4-trifluoromethylphenyl.
 8. The invention of claim 1,wherein X represents a nitrate, sulfate, acetate, tartate, maleate,succinate, citrate, fumarate, aspartate, salicylate, glycerate,ascorbate, fluoride, chloride, iodide, or bromide.
 9. A process forpreparing a 5,6-dihydrodibenzo[a,g]quinolizinium derivative of formula(I), a one or more pharmaceutically acceptable salt of the derivative ora mixture thereof, in which:(a) the compound of formula (IV) isdeprotected to give a compound of formula (V); (b) the compound offormula (V) obtained form the previous step is selectively O-alkylatedwith an alkylating reagent to give a monohydroxy compound of formula(VI); and (c) the compound of formula (VI) thus obtained is reacted withan alkyl substituent (ZCH₂ --X) to give a5,6-dihydrodibenzo[a,g]quinolizinium derivative; ##STR81## wherein, R¹and R², which may be the same or different from each other, represent ahydroxy group or an alkoxy group, having 1 to 4 carbons or R¹ and R²together represent a methylenedioxy group; R³ represents a hydroxy groupor an alkoxy group having 1 to 4 carbons; R⁴ represents an alkyl grouphaving 2 to 8 carbons, or an alkenyl group having 3 to 8 carbons; Xrepresents an inorganic acid ion, an organic acid ion, or a halide; Zrepresents an alkyl group having 5 to 12 carbons, or an alkenyl grouphaving 4 to 6 carbons, a N-benzotriazolyl group, a quinolinyl group, afuryl group, a substituted furyl group, or a group represented by theformula: ##STR82## wherein Z¹, Z², Z³, Z⁴ and Z⁵, which may be the sameor different from each other, represent a hydrogen atom, halogen, analkyl group having 1 to 5 carbons, a trifluoromethyl group, a phenylgroup, a substituted phenyl group, a nitro group, an alkoxy group having1 to 4 carbons, a methylenedioxy group, a trifluoromethoxy group, ahydroxy group, a benzyloxy group, a phenoxy group, a vinyl group, abenzenesulfonylmethyl group or a methoxycarbonyl group; and A and B,which may be the same or different from each other, represent carbon ornitrogen.
 10. A process for preparing a5,6-dihydrodibenzo[a,g]quinolizinium derivative, one or morepharmaceutically acceptable salt of the derivative or a mixture thereof,in which:(a) a compound of the formula (IV) is subjected to pyrolysis ina nitrogen atmosphere in the presence of a non-polar solvent or in theabsence of a solvent at a high temperature of 180 to 300° C. to give acompound of the formula (VI); and (b) the compound of formula (VI) isthen reacted with an electrophile (ZCH₂ --X) to give a5,6-dihydrodibenzo[a,g]quinolizinium derivative of the formula (I);##STR83## wherein, R¹ and R², which may be the same or different fromeach other, represent a hydroxy group or an alkoxy group having 1 to 4carbons or R¹ and R² together represent a methylenedioxy group; R³represents a hydroxy group or an alkoxy group having 1 to 4 carbons; R⁴represents an alkyl group having 2 to 8 carbons, or an alkenyl grouphaving 3 to 8 carbons; X represents an inorganic acid ion, an organicacid ion, or a halide; Z represents an alkyl group having 5 to 12carbons, or an alkenyl group having 4 to 6 carbons, a N-benzotriazolylgroup, a quinolinyl group, a furyl group, a substituted furyl group, ora group represented by the formula: ##STR84## wherein Z¹, Z², Z³, Z⁴ andZ⁵, which may be the same or different from each other, represent ahydrogen atom, halogen, an alkyl group having 1 to 5 carbons, atrifluoromethyl group, a phenyl group, a substituted phenyl group, anitro group, an alkoxy group having 1 to 4 carbons, a methylenedioxygroup, a trifluoromethoxy group, a hydroxy group, a benzyloxy group, aphenoxy group, a vinyl group, a benzenesulfonylmethyl group or amethoxycarbonyl group; and A and B, which may be the same or differentfrom each other, represent carbon or nitrogen.
 11. The process of claim10 wherein the compound of the formula (VI) is reacted with saidelectrophile in the presence of a solvent.
 12. A process fortransforming a 5,6-dihydrodibenzo[a,g]quinolizinium salt of formula (I)into a halide, sulfate, nitrate, acetate, cinnamate, tinate, tannate,maleate, succinate, citrate, fumarate, or fatty acid salt in which(a) acompound of the formula (I) is reacted with acetone in the presence of abase to give a compound of the formula (IX); and (b) the compound of theformula (IX) is reacted with an inorganic acid, organic acid or fattyacid of the formula H--Y to give a compound of the formula (X);##STR85## wherein, R¹ and R², which may be the same or different fromeach other, represent a hydroxy group or an alkoxy group having 1 to 4carbons or R¹ and R² together represent a methylenedioxy group; R³represents a hydroxy group or an alkoxy group having 1 to 4 carbons; R⁴represents an alkyl group having 2 to 8 carbons, or an alkenyl grouphaving 3 to 8 carbons; X represents an inorganic acid ion, an organicacid ion, or a halide; Z represents an alkyl group having 5 to 12carbons, or an alkenyl group having 4 to 6 carbons, a N-benzotriazolylgroup, a quinolinyl group, a furyl group, a substituted furyl group, ora group represented by the formula: ##STR86## wherein Z¹, Z², Z³, Z⁴ andZ⁵, which may be the same or different from each other, represent ahydrogen atom, halogen, an alkyl group having 1 to 5 carbons, atrifluoromethyl group, a phenyl group, a substituted phenyl group, anitro group, an alkoxy group having 1 to 4 carbons, a methylenedioxygroup, a trifluoromethoxy group, a hydroxy group, a benzyloxy group, aphenoxy group, a vinyl group, a benzenesulfonylmethyl group or amethoxycarbonyl group; A and B, which may be the same or different fromeach other, represent carbon or nitrogen; and wherein Y represents ahalide, sulfate, nitrate, acetate, cinnamate, tinate, tannate, maleate,succinate, citrate, fumarate, or fatty acid salt ion.
 13. The process ofclaim 12 wherein the base is sodium hydroxide.